SK285135B6 - 1,3-Propane diol derivative and its use - Google Patents

Abstract

Described is 1,3-propane diol derivative of structure (I), where R1 comprises an acyl group or aliphatic alcohol group derived from C12-30 preferably C16-30 fatty acid with two or more cis or trans double bonds and R2 is hydrogen or comprises an acyl group or aliphatic alcohol group as R1 the same or different, any other nutrient, drug or other bioactive residue for the manufacture of a medicament. There is also described the use of the 1,3-propane diol derivative for the manufacture of a medicament for therapy involving transport of a drug across lipid membranes.

Description

Technical field

The present invention relates to a 1,3-propanediol derivative of the structure defined below for use as a medicament. Also described is the use of such a 1,3-propanediol derivative for the manufacture of a medicament for treatment involving the transport of a medicament or other active agent across lipid membranes.

BACKGROUND OF THE INVENTION

Published patent and basic literature discloses material on certain natural specific diol derivatives and the nutritional and pharmaceutical uses of certain specific diol esters. The source document in the basic literature is Bergelson et al. [Biochim. Biophys. Acta, 116, 511-520 (1966)] describing, inter alia, long chain 1,3-propanediol diesters. There is little to be said about the acid component, but dioleates are described. Proposed edible oil imitations suggested in the patent literature are, for example, proposed by Nabisc in EPA-0 405 873 and EPA-0 405 874, which include linolenic acid esters (the term "a" isomer unless otherwise stated) and arachidonic acid esters and , apparently, 1,4-butanediol. British patent (Unilever) no. 2,161,477 (equivalent to EPA 0 161 114) relates to growth and economic profit from plants using, inter alia, 1,3-propanediol esters and linoleic acid and linolenic acid (again definitely the α-isomer). Anti-ulcer drugs based on 2,3-butanediol esters are described in EPA-0 056 189 (SS Pharmaceutical Co.). The various pharmaceutical effects of 1,3-propanediol esters and short-chain fatty acids are described in EPA-0 018 342 (Sanofi). Somewhat distantly, K. K. Terumo, in EPA-0 222 155, associates 5-fluorouracil with α-linolenic acid, dihomo-gamma-linolenic acid or icosapentenoic acid via the -CH (R) -O- group, where R is methyl, etc. such as, inter alia, anticancer agents.

Lipid barriers

Many drugs act on the surface of cell membranes by associating with cell surface receptors or alternatively delivered to cells by specific delivery systems. However, there are a number of drugs that, despite acting inside cells by altering one of many different functions, such as nucleic acid functions, acting intracellular enzymes, or the behavior of systems such as lysozymes or microtubule systems are unable to efficiently pass into the cell. There may be no receptors and delivery systems with which they can bind, or these systems may deliver the drug to the cell at a rate less than optimal. Similarly, drugs can cross intracellular membranes, such as mitochondrial and nuclear membranes, at a rate that is less than optimal.

There are other barriers to drug movement that are considered important. One particularly important is the blood-brain barrier, which has many characteristics of a cell membrane. There are a number of drugs where there are difficulties in achieving adequate brain concentrations due to this barrier. Next is the skin: a few years ago, the drugs were applied to the skin only for the purpose of acting on the skin. However, it has been found that the skin may be a suitable route for delivering systemic drugs to the body, and as a result more and more compounds are administered by various techniques through patches.

All three types of barriers, cell membrane and intracellular membrane, blood-brain barrier and skin have an important common feature in that they are essentially composed of lipids. That is, they are impermeable to the primary water-soluble drugs if these drugs cannot pass through the membrane via the receptor or delivery system. In contrast, lipophilic agents are able to cross these barriers much more easily without the need for any specific receptor or transport system.

Classes of biologically active substances that require crossing the lipid barriers.

Drugs whose pharmacokinetic behavior can be improved by increasing the lipophilicity reported by the route of entry are:

L Cell entry: drugs that are primarily intracellularly active are likely to be particularly useful. These drugs include:

(a) all anti-inflammatory medicinal products, whether steroidal or non-steroidal;

b) all cytotoxic drugs used in the treatment of cancer;

c) all antiviral drugs;

(d) all other medicinal products which must enter cells in order to obtain optimal effects, in particular medicinal products which act on DNA or RNA, or on enzymes located intracellularly, or on secondary mesenger systems, or on microtubules, mitochondria, lysosomes or other intracellular organelles;

e) steroid hormones and other hormones that act intracellularly, such as estrogens, progestins, androgenic hormones, and dehydroepiandrosterone.

2. Blood-brain barrier: all drugs acting on the central nervous systems will have their transport improved in this way. It includes all drugs used in psychiatry, all drugs used in cerebral infections in any organism or in cerebral carcinoma and all other drugs acting on nerve cells such as antiepileptic drugs and other drugs acting on neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and other.

3. Skin: as in the blood-brain barrier, all drugs that may be required to penetrate the skin to achieve a systemic effect will benefit from their conversion to fatty acid derivatives.

For example, the approach discussed is applicable to amino acids. Of particular interest are those that appear to play a role in regulating cellular functions as well as acting as components of proteins. Examples include tryptophan (a precursor of 5-hydroxytryptamine [5-TH], a key regulator of nerve and muscle function), phenylalanine (a precursor of catecholamines) and arginine (a regulator of nitric oxide synthesis, which also plays an important role in controlling cellular activities).

General characteristics

The compounds disclosed herein generally have many advantages in addition to their lipophilicity. Two units of a given fatty acid or even one unit can be administered in a form that is readily introduced into the body in the form of an oral, parenteral or topical composition; which is very well tolerated without associated side effects, for example with free fatty acids; which is not very stable to be used; which may not have a chiral center; and which is easier to synthesize than the corresponding triglycerides with three attached units of the same fatty acids. Because triglycerides are well tolerated and well used, they are less suitable than the proposed compounds because they are poorly synthesized and may have a chiral center with a number of potential isomers. In addition, with triglycerides, fatty acids can relatively easily migrate from one position to another to form new molecules that were not present in the original preparation. This appears to be a problem, particularly in the context of drug approval, where such instability may be unacceptable.

In addition, when two different fatty acids are to be delivered, these advantages are afforded by the possibility of simultaneously administering two substances with different biological effects in one molecule. This avoids the approval problems that arise when two substances are administered as separate compounds, as well as issues that arise with the possible presence of chiral centers. When two drugs are administered as separate molecules, the approval authorities routinely require that each drug be examined separately as well as in combination. When combined in one molecule, only one molecule needs to be studied, which greatly reduces drug development costs.

If other active substances other than fatty acids are present, this presents similar advantages. The compounds allow the drugs or other compounds to be administered in the form of relatively lipophilic compounds that are not chiral (unless the drugs or other compounds are themselves chiral), which release the active ingredients relatively easily and which are well tolerated by oral, local or parenteral administration. Their lipophilicity allows them to be absorbed partially through the lymphatic system, i.e. without passing through the liver; to cause less gastrointestinal irritation than many compounds; and to facilitate the transport of drugs and other preparations across lipophilic barriers such as the skin, cell membrane, and blood-brain barrier.

There is evidence that, besides accelerating the passage of lipid barriers, many drugs can acquire interesting specific properties if they become more lipophilic. These properties include prolongation of exposure time, reduction of side effects, especially gastrointestinal, avoidance of early hepatic metabolism, and potentially site-specific administration of various agents.

Fatty acid derivatives; effects of fatty acids

The transport of the active substances through the lipid membranes can be improved by binding them directly or via an intermediate to, in particular, gamma-linolenic acid (GLA) or dihomogammolinolenic acid (DGLA), two fatty acids which in themselves have a number of desirable effects. These linkages also allow biologically active substances to be delivered together in the same molecule with fatty acids, which themselves have the desired effects, notwithstanding the advantages of transport. Other fatty acids such as any essential fatty acids (EFAs), and in particular the twelve natural acids of the n-6 and n-3 series of EFAs, can be used (Figure 1). Of these twelve essential fatty acids, arachidonic acid, adrenic acid, stearidonic acid, icosapentenic acid and docosahexenic acid are of particular interest since they themselves have the desired effects. In addition, any fatty acids, preferably those containing 12 to 30 carbon atoms or 16 to 30 carbon atoms, and preferably having at least two cis- or trans-carbon-carbon double bonds, may be used. The fatty acid or the corresponding aliphatic alcohol may be used. The conjugated linoleic and columbinic acids are examples of fatty acids which in themselves have valuable properties and are likely to be particularly suitable for use. References to fatty acids are therefore to be understood here as to both forms, except when the chemical structure of one or the other is particularly discussed. However, the advantageous properties of GLA and DGLA make them particularly valuable for this purpose.

Essential fatty acids, which are essentially all in the cis configuration, are systematically named as derivatives corresponding to octadecanoic, icosanoic or docosanoic acid, for example z, z-octadeca-9,12-dienoic acid or z, z, z, z , z-dokoza-4,7,10,13,16,19-hexenoic acid, but suitable numerical determination is based on the number of carbon atoms, the number of unsaturation centers and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as 18: 2n-6 or 22: 6n-3. In some cases, initial letters and abbreviated forms of names, such as EPA for icosapentenoic acid, are also used as trivial names.

Figure 1 n-6 EFA series n-3 EFA series (linoleic acid, LA) (α-linolenic acid, ALA)

18: 3n-6 (γ-linolenic acid,

GLA) (stearidonic acid, SA) extension

20: 4n-3 (dihomo-γ-quinolenic acid, DGLA)

20: 4n-6 (arachidonic acid.

AA) (icosapentaenoic acid.

Extension

22: 4n-6 (adrenic acid) δ-4-desaturase docosahexaenoic, DHA)

GLA and DGLA

GLA and DGLA have been specifically shown to have anti-inflammatory effects, lower blood pressure, inhibit platelet aggregation, lower cholesterol levels, inhibit cancer cell growth, reduce dyskinetic movements, reduce breast pain, improve calcium absorption and increase bone deposition , reduce the harmful effects of ionizing radiation, treat various mental illnesses, cause vasodilation, improve kidney function, treat diabetic complications, widen blood vessels, and so on. GLA and DGLA-linked active substances will therefore not only become more lipophilic, with increased ability to cross all membranes, skin and blood-brain barrier, but are also likely to have new and other therapeutic effects. Thus, the fatty acid compounds may be mutually supporting two-member prodrugs (if directly linked) or mutually supporting three-member prodrugs (if linked by a linker).

Other fatty acids likely to be of particular value in this context are arachidonic acid and docosahexenic acid, which are the major components of all cell membranes; adrenic acid; and stearidonic acid and icosapentenoic acid, which have a number of suitable properties similar to those of GLA and DGLA. Fatty acids not included in the fatty acids shown in Figure 1 of particular interest are conjugated linoleic acid (cLA) and columbinic acid (cA). cLA has a number of interesting effects in the treatment and prevention of cancer, in promoting the growth of particularly protein-containing tissues, in the prevention and treatment of cardiovascular diseases and as an antioxidant. cA has many properties of essential fatty acids.

Classes of active substances which interact with biologically active fatty acids

The types of active substances to be incorporated into the compounds as mentioned herein may be divided into:

(a) Medicines including antibiotics, antiprotozoa, antipsychotics, antidepressants and NSA1D and compounds used in the treatment of cardiovascular, respiratory, dermatological, psychological, neurological, renal, muscular, gastrointestinal, reproductive and other diseases and cancer.

(b) Hormones.

c) Amino acids.

(d) Vitamins, in particular Group B and other essential nutrients.

e) Cytokines and peptides.

f) Neuromediators and precursors of neuromediators.

g) Groups of phospholipids such as inositol, choline, serine and ethanolamine, which can be linked directly or through the phosphate moiety.

h) Aromatic amino acids such as phenylacetic acid, phenylbutyric acid and cinnamon, which are particularly valuable in the treatment of cancer.

effectiveness

The combination of the therapeutic effect of the drug with the therapeutic effect of the fatty acid may be exemplified by:

a) Psychotropic drugs can be linked to fatty acids such as GLA, DGLA, arachidonic acid, icosapentenic or docosapentenic acid, which play an important role in brain function, thereby providing a double therapeutic effect.

b) Drugs used to treat cardiovascular disease may be associated with a fatty acid that is also valid in this treatment, such as icosapentenoic acid, which lowers triglyceride levels and inhibits platelet aggregation, or GLA or DGLA, which lowers cholesterol and has vasodilator effect, or arachidonic acid, which is a potent cholesterol lowering agent, or DHA, which has antiarrhythmic properties.

c) Drugs used to treat any form of inflammation may be linked to a fatty acid such as gamma-linolenic acid, dihomo-gamma-linolenic acid or icosapentenic acid or docosahexenic acid, which also have an anti-inflammatory effect.

(d) Drugs used for the treatment of osteoporosis may be linked to GLA or DGLA, which increase calcium incorporation into bones, or to EPA or DHA, which reduce calcium excretion via the urinary excretion system.

e) Drugs used in skin diseases can be linked to GLA or DGLA, which have anti-inflammatory effects on the skin.

f) Drugs used in cancer can be linked to GLA, DGLA, arachidonic acid, EPA or DHA, which have anti-cancer effects per se and which can abolish resistance to anti-cancer drugs.

Concepts applied to essential fatty acids as biologically active substances

Essential fatty acids (EFAs) include, as mentioned, and as is well known, a series of twelve compounds. Since linoleic acid, the parent compound of the n-6 series, and α-linolenic acid, the parent compound of the n-3 series, are the major representatives of EFAs in the diet, these substances themselves have a relatively minor role in the body. In order to be completely useful to the body, these parent compounds must be metabolized to longer chain compounds and more unsaturated compounds. In terms of quantity as judged by their level in cell membranes and other lipid reactions, the major metabolites of the n-6 series are dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA), while the major metabolites of the n-3 series are icosapentenoic acid (EPA) and docosahexenic acid (DHA). DGLA, AA, EPA and DHA are important components of most lipids in the body. As important in themselves, they can also provide a wide range of oxygen derivatives, icosanoids, including prostaglandins, leukotrienes, and other compounds. Fatty acids likely to have particular value in therapy are DGLA, AA, EPA and DHA, along with GLA, DGLA precursor, stearidonic acid (SA), EPA and DPA precursor (22: 5n-3), DHA precursor and adrenic acid. .

Furthermore, there are fatty acids such as oleic acid, parinaric acid and columbinic acid, which are not EFAs but have significant effects in the body. One of the most interesting of these is the conjugated linoleic acid mentioned earlier and which has a number of desirable effects.

It has generally been judged, both in nutrition and in the therapy of diseases, that it is sufficient to supply linoleic and α-linolenic acids and the remainder is taken care of by the body's own metabolism. It is now widely accepted that this is not true. Different diseases may have different abnormal patterns of EFAs and due to metabolic problems they cannot be easily corrected by administration of linoleic acid and α-linolenic acid. In many situations, it is then desirable to provide increased amounts of either one of the other EFAs or to deliver two or more EFAs simultaneously. While EFAs can be delivered in various forms and in various compositions, it is desirable to supply fatty acids as particular molecules in both nutrition and medical treatment. Likewise, in various situations, it may be desirable to give EFA or another fatty acid in conjunction with an amino acid, a vitamin, a drug, or another molecule that in itself has the desired properties.

Until now, it has been proposed to administer two fatty acids simultaneously for particular triglycerides following the natural occurrence of essential fatty acids in the form of triglycerides. However, triglycerides, in addition to the symmetrical around the carbon at the 2-position, are chiral and this fact, coupled with the migration of acyl between the α and β positions, makes the synthesis of specific triglycerides a serious problem. This migration can take place after synthesis, creating particular problems in the context of drug approval. The lack of specificity when two fatty acids are present in the same triglyceride molecule causes many problems in synthesis, pharmacology, formulation and stability. In addition, triglycerides may have a difficult and slow synthesis. When processed under similar conditions, the propanediol derivatives can be produced much faster.

Thus, the use of diol esters is desirable for the convenient administration of various fatty acids simultaneously, or individual fatty acids in high amounts in a well tolerated form.

Chemical nature of biologically active substances which can be derivatized according to the invention

This part of the description covers biologically active derivatives of fatty acids (or aliphatic alcohols) with an accessible carboxylic, alcohol or amine group, so that a simple, well defined chemical unit is formed. The linkage may be direct to provide two-component compounds, or it may be spatially arranged with a suitable linking group, giving the three-component compounds with respect to the number of moieties into which the compounds are divided.

Classes of biologically active substances according to their chemical structure

Among the classes of compounds are those mentioned, wherein n is usually 1 to 3. The compounds claimed herein include diesters of class a) ii); n third Substances in which n is greater or less, or where the bonds are not ester bonds, may have meaning for similar reasons and are described, but for the most part not claimed.

a) Biologically active substances with a free carboxyl group - these substances can be derivatized as follows

(i) an ester bond with an unsaturated aliphatic alcohol (UFA)

ABOUT

ii) an ester bond with an unsaturated fatty acid ω-hydroxyalkyl ester

iii) an unsaturated aliphatic alcohol ω-hydroxylakylcarboxy ester ester o

(b) biologically active substances with a free hydroxyl group - these substances may be derivatized as follows:

i) an ester linkage with an unsaturated fatty acid

ii) an unsaturated aliphatic alcohol ester bond with the ω-carboxyalkylcarboxy ester

(iii) an ester bond with an unsaturated fatty acid ω-carboxyalkyl ester

iv) a phosphate ester bond with an unsaturated fatty acid ω-hydroxyalkyl ester

R = H, CH ₃ or a cationic counterion

(c) biologically active substances with a free amino group - these substances may be derivatized as follows:

i) an amide bond with an essential fatty acid

ii) an amide bond with the ω-carboxylakylcarboxyester of an essential aliphatic alcohol

(iii) an amide bond with the essential fatty acid ω-carboxyalkyl ester θν co

In all of the above categories, where n is preferably 1 to 3, the carbon chain of the unsaturated fatty acid or unsaturated aliphatic alcohol is represented by

Reported residue of biologically active substance

In all these categories, the terms "unsaturated fatty acid" (and derived "unsaturated aliphatic alcohol") represent a member of the group consisting of oleic acid (and oleoyl alcohol) and any fatty acid (or the corresponding aliphatic alcohol) with two or more cis or trans double bonds. However, the fatty acids likely to be most valuable in this context are the essential fatty acids shown in Figure 1, and in particular GLA, DGLA, AA, SA, EPA and DHA. Conjugated linoleic acid and columbinic acid may be particularly important for particular purposes.

General discussion on synthesis

The individual fatty acids may be obtained by purification from natural animal, plant or microbial sources, or may be chemically synthesized by methods known to those skilled in the art or hereinafter.

The individual aliphatic alcohols may be prepared by chemical reduction of the fatty acids indicated by methods known to those skilled in the art or hereinafter.

Derivatization of biologically active substances in classes (a),

b) and c) [subclasses ii) and iii)] requires the formation of one or more ester bonds. This chemical process may be achieved by any suitable method of ester synthesis, and in particular:

(a) reaction of the alcohol with an acid chloride, an acid anhydride or a suitably activated ester with or in the absence of an organic tertiary base such as pyridine in a suitable inert solvent such as dichloromethane at a temperature between 0 and 120 ° C;

b) reacting the alcohol with an acid or an alkyl ester of short or medium chain length in the presence of a suitable acid catalyst, for example 4-toluenesulfonic acid, with or without a suitable inert solvent, for example toluene, at a temperature between 50 and 180 ° C reaction water, for example under vacuum,

c) reacting the alcohol with an acid in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide, in or in the absence of a suitable organic tertiary base such as 4- (N, N-dimethylaminopyridine) in an inert solvent such as dichloromethane at a temperature between 0 and 50 ° C

d) reacting the alcohol with an acid or short or medium chain alkyl ester or an activated acid ester such as a vinyl ester in the presence of a hydrolase enzyme such as a porcine liver esterase in or without a suitable solvent such as hexane at temperatures between 20 and 80 ° C under conditions such that water or alcohol or an aldehyde by-product is removed, for example under vacuum,

c) reacting the acid with a suitable alcohol derivative, for example iodide, in or in the absence of a suitable base, for example potassium carbonate, in a suitable inert solvent, for example dimethylformamide, at a temperature between 0 and 80 ° C,

f) reacting the alcohol with a short or medium chain alkyl ester in the presence of a catalytic amount of an M ⁺ OY 'type alkoxide, wherein M is an alkali or alkaline earth metal such as sodium, Y is an alkyl group containing 1 to 4 carbon atoms which it may be branched, unbranched, saturated or unsaturated, in or in the absence of a suitable solvent, for example toluene, at temperatures between 50 and 180 ° C such that the lower alcohol of formula HOY is removed from the reaction mixture, for example under vacuum.

Derivatization of biologically active substances of class c) requires the formation of an amide bond. This can be achieved by any suitable amide synthesis method, in particular:

g) reaction of the amine with an acid chloride, an acid anhydride or a suitably activated ester in or in the absence of an organic tertiary base such as pyridine in a suitable inert solvent such as dichloromethane at a temperature between 0 and 120 ° C,

h) reacting the amine with an acid in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide, in or without a suitable organic tertiary base such as 4- (N, N-dimethylaminopyridine) in an inert solvent such as dichloromethane at a temperature between 0 and 50 ° C

(i) reacting the amine with a short or medium chain alkyl or short-chain alkyl ester or an activated acid ester such as a vinyl ester in the presence of a hydrolase enzyme such as a pig liver esterase in or without a suitable solvent such as hexane at temperatures between 20 and 80 ° C under such conditions that water or an alcohol or aldehyde by-product is removed, for example under vacuum.

Derivatization of biologically active substances in class b) iv) requires the formation of phosphate ester bonds. This chemical process can be achieved by any suitable method of phosphate ester synthesis, in particular:

j) reacting an alcohol (e.g., UFA, 3-hydroxypropyl ether) with a suitable activated phosphate derivative (e.g., POCl 3) with a tertiary base (e.g., Et ₃ N) in a suitable solvent (e.g., tetrahydrofuran) at less than 10 ° C to give crude phosphophosphoric acid. This is followed by the reaction of an alcohol (e.g. atocopherol) with a crude tertiary phosphide chloride with a tertiary base (e.g. Et 3 N) in a suitable solvent (e.g. tetrahydrofuran) at about room temperature to give the crude phosphorochloridate. This can be hydrolyzed (for example by adding water and Et ₃ N) to form a phosphodiester. Alternatively, the addition of methanol provides a phosphotriester which can be demethylated using a suitable nucleophile (e.g., lithium bromide) in a suitable solvent (e.g., methyl ethyl ketone) to form a phosphodiester,

k) reacting a phosphomonoester (e.g. phosphate UFA, 3-hydroxypropyl ester) with an alcohol (e.g. choline) in the presence of a condensing agent (e.g. 1,3-dicyclohexylcarbodiimide) in a suitable solvent at an appropriate temperature,

(l) the phospholipidase reaction catalyzed by a phospholipase D catalyzed reaction of 2-deoxy-2-lysophosphatidylcholine with a primary or secondary alcohol.

Of course, chemistry generally depends, of course, on the nature of the compounds to be bound and whether the bonds are direct or indirect. For example, fatty acid pairs may be bonded directly as fatty acid esters of an aliphatic alcohol or as anhydrides, and when diol linkers are used, ether linkages to aliphatic alcohols are an alternative to the more general, more common ester bonds to fatty acids per se. In all cases, the bonds may again be known per se in the art of chemistry.

Examples of active substance pairs that may be bound either directly or via a linker, in particular a 1,3-propanediol bond.

The following examples of active compound pairs and resulting compounds are predominantly new to the knowledge of the patent owner. If so, they constitute part of the invention as new chemical units, as well as new in their use in the treatment or prevention of disease, whether directly claimed or not.

Fatty acids

GLA-OA (OA = oleic acid); GLA-GLA; EPA-EPA; GLA-EPA; GLA-DHA; AA-DHA; AA-EPA; GLA-AA; GLA-SA; SA-DHA; DGLA-DGLA, DGLA-GLA, DGLA-SA, DGLA-AA, DGLA-EPA, DGLA-DHA, AA-AA, EPA-SA, EPA-DHA, DIIA-DHA, cLA-cLA, cLA-GLA, cLA- DGLA, CA-AA, CA-SA, CA-EPA, CA-DHA, CA-CA, CA-GLA, CA-DGLA, CA-AA, CA-SA, CA-EPA, CA-DHA.

vitamins

GLA-niacin, GLA-retinoic acid, GLA-retinol, GLA-pyridoxal, di-GLA-pyridoxine, di-EPA-pyridoxal and generally any of, for example, GLA, DGLA, AA, SA, EPA or DHA with any vitamin including ascorbic acid , vitamin D and its derivatives and analogs, vitamin E and its derivatives and analogs, vitamin K and its derivatives and analogs, vitamin B) (thiamine), vitamin B ₂ (riboflavin), folic acid and related pterins, vitamin B ₁₂ , biotin and pantothenic acid.

amino acids

GLA-tryptophan, GLA-proline, GLA-arginine, GLA- or DHA-phenylalanine, GLA-GABA, GLA-aminolevulinic acid and generally any of, for example, GLA, DGLA, AA, SA, EPA or DHA with any natural amino acid or related compound such as taurine and carnitine.

SK 285135-6

Aromatic acids

GLA-phenylbutyric acid, GLA-phenylacetic acid, GLA-trans-cinnamic acid and generally any for example GLA, DGLA, AA, SA, EPA or DHA with any arylalkanoic or arylalkenoic acid.

steroids

GLA-hydrocortisone, GLA-estradiol, GLA- and DHA-dehydroepiandrosterone and generally any of, for example, GLA, DGLA, AA, SA, EPA or DHA with any natural or synthetic steroid such as any estrogen, any progestin, any adrenal steroid and any an anti-inflammatory steroid, in particular betamethasone, prednisone, prednisolone, triamcionolone, budesonide, clobetazole, beclomethasone and other related steroids.

antioxidants

GLA-lipoic acid, DHA-lipoic acid, GLA-tocopherol, di-GLA-3,3'-thiodipropionic acid and generally any of, for example, GLA, DGLA, AA, SA, EPA or DHA with any natural or synthetic antioxidant with which they may be chemically bound. This includes phenolic antioxidants (eg eugenol, camosic acid, caffeic acid, BHT, gallic acid, tocopherols, tocotrienols and flavonoid antioxidants (eg myricetin, fisetin)) polyenes (eg retinoic acid), unsaturated sterols (eg ⁵ -avenosterol), organoseme compounds (e.g. allicin), terpenes (e.g. geraniol, abietic acid) and amino acid antioxidants (e.g. cysteine, camosine).

Healing

GLA and indomethacin, ibuprofen, fluoxetine, ampicillin, penicillin V, sulindac, salicylic acid, metronidazole, flufenazine, dapson, tranylcypromine, acetylcamitin, haloperidol, mepacrine, chloroquine, penicillin, tetracyclic acid, pamastinide, pravastatide, pravastatid, clordronic and their sodium salts, adenosylsuccinate and adenylsuccinate, and related compounds and agents used as X-ray contrast media and generally any of, for example, GLA, DGLA, AA, SA, EPA or DHA with any drug, especially any drug used to treat infections, inflammatory diseases involving various forms of arthritis, cancer, cardiovascular, respiratory, dermatological, psychological, neurological, muscular, renal, gastrointestinal reproductive and other diseases.

Concepts applied to NSAIDs; reported efficiencies

As a special case of the concepts discussed, derivatives of various non-steroidal anti-inflammatory drugs (NSAIDs), and in particular indomethacin ester and GLA, were prepared. Indomethacin as a non-steroidal anti-inflammatory drug is believed to have a primary intracellular mechanism of action by inhibiting the enzyme cyclooxygenase, which converts arachidonic acid to the anti-inflammatory metabolites of prostaglandin.

Indomethacin is known to penetrate cells very poorly, and thus must be administered at relatively high doses that result in side effects, therefore the ability to cross cells in indomethacin-GLA and indomethacin alone was compared using the normal fibroblast line, breast cancer line and malignant melanoma line.

The results are shown in EPA-0 675 103 and show that in all cell lines the intracellular concentrations of indomethacin after incubation with indomethacin are very low and mostly detected only in trace amounts. In contrast, again for all cell lines, incubation with indomethacin-GLA provides very substantial amounts of both indomethacin-GLA and free indomethacin found within the cells. These results show unequivocally that the GLA ester and indomethacin penetrate cells efficiently, then it is de-esterified intracellularly to obtain free indomethacin, and that due to the many similarities between the cell membrane barrier and the blood-brain and skin barrier, indomethacin-GLA will also be effective in accelerating penetration indomethacin ccz these barriers. This permeation and cleavage to release the active ingredients is contemplated for all compounds disclosed herein.

SUMMARY OF THE INVENTION

The present invention provides a 1,3-propanediol derivative of structure (I)

CH ₂ OR 1

CH ₂ O ·

I,

CH ₂ OR 2 in which

R ¹ summarizes an acyl group or an aliphatic alcohol group derived from a C 12 to C 30 fatty acid, preferably a C 16 to C 30 carbon atom having two or more cis- or trans-double bonds, and

R ² is a hydrogen atom or includes an acyl group, or an aliphatic alcohol group such as R ¹ , the same or different, or a residue of a nutritional substance, a drug or other biologically active residue, for use as a medicament.

A preferred embodiment of the present invention is a 1,3-propanediol derivative in which a phosphate, succinate or other difunctional acidic group is interposed between the group R ¹ and / or R * and the residue of 1,3-propanediol, especially when R ² is a nutritional residue, a drug or other biologically active substance having a hydroxyl group or an amine functional group.

Another preferred embodiment of the invention is a 1,3-propanediol derivative in which the group is derived from a fatty acid which is an essential fatty acid n-6 or n-3 series or oleic acid, columbinic acid or parinaric acid, or conjugated linoleic acid, in particular a 1,3-propanediol derivative in which the group is derived from a fatty acid which is gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, stearidonic acid, icosapentenoic acid, n-3 docosapentenoic acid, acid docosahexenic or conjugated linoleic acid.

Preferred is the use of any of the defined 1,3-propanediol derivatives for the manufacture of a medicament for the treatment, which comprises transporting the medicament or other active agent through the lipid membranes.

A preferred embodiment of the invention is a 1,3-propanediol derivative comprising two fatty acid residues, one fatty acid being gamma-linolenic acid or dihomo-gamma-linolenic acid, and the other being gamma-linolenic acid or dihomo-gamma acid -linolenic acid, stearidonic acid, icosapentenic acid, docosahexenic acid, conjugated acid

Selina linoleic or columbinic acid for use as a medicament for the treatment of:

(a) complications of diabetes, in particular neuropathy and retinopathy; and improving insulin responses in diabetes and pre-diabetes;

b) cancers;

(c) osteoarthritis;

d) rheumatoid arthritis;

(e) other inflammatory and autoimmune diseases including Sjogren's syndrome, systemic lupus, ulcerative colitis, Crohn's disease and uveitis;

(f) respiratory diseases including asthma;

(g) neurological disorders, including multiple sclerosis;

Parkinson's disease and Huntington's chorea;

h) renal and urinary disorders;

(i) cardiovascular diseases;

j) degenerative eye diseases including retinitis pigmentosa and senile macular degeneration;

(k) mental illnesses, including schizophrenia, Alzheimer's, concentration disorders, alcoholism and depression;

l) prostatic hypertrophy and prostatitis;

(m) impotence and male infertility;

n) mastalgia;

o) male baldness;

p) osteoporosis;

(q) dermatological disorders, including atopic eczema, hand eczema, psoriasis, urticaria and allergic disorders;

(r) dyslexia and other learning disabilities;

s) cancer cachexia.

Another preferred embodiment of the present invention is a 1,3-propanediol derivative comprising two fatty acid moieties, one fatty acid being arachidonic acid and the other being arachidonic acid, gamma-linolenic acid, docosahexenic acid, dihomo-gamma- linolenic or icosapentenic acid for use as a medicament for the treatment of said disorders and in particular a), g), i), j), k), q) and ar).

Another preferred embodiment of the present invention is a 1,3-propanediol derivative comprising two fatty acid moieties, one fatty acid being icosapentenic acid and the other being icosapentenic acid or docosahexenic acid for use as a medicament for the treatment of any of these disorders, but separately

(b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (p), (r) and (s).

The present invention also relates to said 1,3-propanediol derivative for the use of the diol moiety contained therein as a food ingredient, in particular a functional food or nutraceutical for health promotion, as a dietary supplement or as a food additive.

The invention is also described to a broader extent, covering a wide range of active substances releasable in the body.

It is understood that the present invention relates to biologically active substances, and the term includes a drug, an essential nutritional substance or other compound to be introduced into the human or animal body in therapy or for maintaining health.

The invention relates to biologically active substances in a form in which they are lipophilic so that they can readily cross lipid barriers in the body, or two of these biologically active substances in the same molecule (wherein at least one of the biologically active substances is a fatty acid or aliphatic alcohol), or biologically The active ingredients are in a form that serves both the objectives and / or facilitates the easy synthesis of these compounds without a chiral center. From the viewpoint of drug regulation, it is very advantageous to have two biologically active substances present in one molecule rather than in two separate units. Advantages may also consist in providing known biologically active substances in new ways. These advantages include increased lipophilicity, the additive effects of two biologically active agents that are not normally present at the same time, and sometimes the synergistic effects of these biologically active agents.

The invention relates to the coupling of biologically active agents using certain binding molecules, which are described in detail hereinafter, and to the synthesis of a number of compounds, some of which are novel, while others are novel in terms of their usefulness in therapy and / or in maintaining health. However, reference is also made to compounds using other binding molecules that are not currently claimed and to directly associated biologically active substances such as those described in e.g. in published application EPA-0 393 920 for fatty acids and antiviral agents, and in related application EP-95301315.8 (published as EPA-0 675 103) for fatty acids and non-steroidal anti-inflammatory drugs.

The compounds are generally active substances bearing an acidic function esterified directly by the diol moiety, but, for example, in an aliphatic alcohol or other active substance bearing hydroxyl functional groups, it can be interposed between R ¹ and / or R ² and the 1,3-propanediol residue phosphate, succinate or another difunctional acid group, especially when R ² is a residue of a nutrient, drug or other biologically active substance with a hydroxyl or amine function.

While the direct linkages of biologically active substances and fatty acids (class a) [i], b) [i] and c) [i] are described, the present invention relates primarily to class a) [ii], n = 3, wherein biologically active substances, which may be fatty acids themselves, are associated with fatty acids such as 1,3-propanediol diesters, and of class b) (iv), n = 3, with biologically active substances which may be aliphatic alcohols alone or 3- hydroxypropyl esters of fatty acids are linked by a phosphate bond to the monoester of the fatty acid and 1,3-propanediol. This diol can also be considered as 2-deoxyglycerol and the corresponding diesters as 2-deoxy-1,3-diglycerides. Compounds in class b) iv), n = 3, are also based on 1,3-propanediol and can be considered 2-deoxy-2-lysophospholipids. The compounds disclosed herein are almost all new chemical units, or at least never before, have been used in the treatment of animal or human diseases.

As a compound, diol is used as a linker widely described in the literature among many other diols, but the patentees have found that its use in therapy as an essential fatty acid diester or as a compound with an essential fatty acid in one position and a biologically active substance is an essential fatty acid) in the other, it is both unwritten and particularly important. It provides a convenient route to provide a single fatty acid as a monoester or diester when a fully defined compound is desired, or there is no chiral center present, such as in glycerol-1 (3) monoesters and diglycerides (α, β and 1,3 wherein the fatty acid at position 1 is different from that at position 3), nor does the spatial isomer exist. Moreover, apart from the administration of individual acids, these mono- and diesters may be valuable in the pharmaceutical composition as emulsifiers. The structure of 1,3-propanediol is close to glycerol of natural triglycerides and is an efficient and safe delivery system. Moreover, it allows easy and unambiguous synthesis of the defined compounds without the problem of migration of acyls occurring in triglycerides and without complications with optical isomers. For example, the proprietors of this patent have shown that intravenous infusion and oral administration of a 1,3-propanediol diester emulsion and GLA / EPA results in rapid release of free GLA and EPA in vivo and further metabolism of GLA and AA and EPA to DHA. Similarly, diesters GLA-GLA and EPA-EPA and diesters niacin-GLA and indomethacin-GLA have been shown to be absorbed after oral administration and release their active ingredients.

In addition, as far as the patentees are aware, all of said 1,3-propanediol-derived compounds (corresponding to pages 17, 18 and 19 of published PCT / GB96 / 01053, WO 96/34846) are novel compounds that have not been previously described. The specific diols of the two fatty acids and diols wherein the fatty acids selected from the group consisting of GLA, DGLA, AA, SA, EPA, DHA cLA and CA are present in one position and the other is a vitamin, amino acid, aromatic acid, steroid, antioxidant or another drug is a new substance.

Fatty acid diesters have a wide range of possible uses. They can be used as pharmaceutical compositions for the treatment or prevention of diseases in which fatty acid abnormalities have been identified. They can be added to foods or added to nutritional supplements, or used as nutritional supplements for those who require a particular fatty acid to treat or prevent diseases. They may also be used in foods or pharmaceutical compositions for veterinary use. They can also be used for skin care.

The present invention provides the following advantages or various aspects including those encompassed by the following claims:

i) An acceptable and safe route of administration for therapeutic or nutritional purposes, one or two components of the unsaturated fatty acid or one unsaturated fatty acid and one non-fatty acid biologically active substance.

(ii) A biologically active substance derivative for overcoming lipid membranes in the body to show its activity, whether in cell entry or through the skin, blood-brain barrier or other barrier, by combining 1,3-propanediol and an essential fatty acid of natural series n-6 or n -3 and in particular GLA or DGLA, AA, SA, EPA or DHA, or related fatty acids cLA, or CA.

iii) A fatty acid derivative and a drug such that the drug and the fatty acid are mutually effective.

iv) A method of improving drug delivery across lipid membranes in the body, characterized by administering the drug in said form.

v) A method of making a pharmaceutical composition for improved therapy comprising transporting the drug through lipid membranes in the body, characterized by incorporating the drug in said form into a pharmaceutical composition.

vi) A method for producing a pharmaceutical composition for delivering one or two fatty acids from the group of ii) or for delivering one of these fatty acids in conjunction with another active agent.

Examples of specific compounds have been disclosed; examples of synthesis will be given.

Efficacy and use in general

The particular use of particular groups of compounds is given elsewhere, but the usefulness of 1,3-propanediol diesters can generally be illustrated as follows:

1. Improved fatty acid tolerance. Apart from triglycerides, most forms in which fatty acids, including free acids, salts, ethyl esters and other glycerides can be administered, cause to some extent digestive problems, as evidenced by nausea, vomiting and diarrhea. Propanediol diesters in rat and mouse animal studies were well tolerated. For example, diesters GLA-GLA and GLA-EPA were administered to rats and mice at doses up to 10 g / kg without any signs of diarrhea. This shows that diesters are a very acceptable route for the delivery of biologically active fatty acids.

2. Reduced drug toxicity. Non-steroidal anti-inflammatory drugs such as aspirin and indomethacin are known to have severe gastrointestinal toxicity with intestinal and gastric ulceration and gastrointestinal bleeding. Doses of indomethacin known to cause gastrointestinal ulcers (5 to 30 mg / kg) were administered to fasting rats either in the form of free indomethacin or in the same amount of indomethacin in 1,3-propanediol diester with GLA at the second position. The animals were sacrificed after 24 hours and the entire gastrointestinal tract was examined for ulceration. While large ulceration was observed in animals treated with indomethacin alone, little or no ulceration was observed in animals treated with GLA-indomethacin.

3. Effective delivery of a biologically active form of a fatty acid. GLA was administered in the form of either GLA-GLA or GLA-EPA and EPA was administered in the form of GLA-EPA or EPA-EPA. The diesters were administered either orally by gavage or intravenously in the form of a 20% emulsion made using 2% oat galactolipid as emulsifier at a dose of about 0.1 to 2.0 g / kg. Animals were killed at 1,2,4, 8 and 24 hours and liver, plasma and red blood cells were collected. The presence of unmetabolized diesters was determined by high pressure liquid chromatography. The presence of diester-derived fatty acids and metabolites of these fatty acids was controlled by extracting the lipids from the liver, plasma or red blood cells, separating this lipid fraction into triglycerides, phospholipids, cholesterol esters and free fatty acids by thin-layer chromatography, methylation of these fatty acids. separated fractions and analyzing these fatty acids using gas chromatography using methods described in the literature. These experiments have shown that after oral administration, about 10% of the administered diesters can be identified as diesters. Most of the GLA or EPA was found to be free fatty acid or phospholipid and to a lesser extent than cholesterol ester and in trilyceride fractions. Moreover, especially in the phospholipid fractions, metabolites of GLA, DGLA and arachidonic acid and metabolites of EPA, docosapentenoic acid and DHA can be found in increased amounts. These observations indicate that fatty acids are readily released from the diester form and are further metabolized to biologically active substances. Similar results were obtained with intravenous administration of diesters except that after one hour about 40% of the diesters remain in their original form and free fatty acids are released, metabolized and incorporated into other lipid fractions over the next 24 hours. It is possible that the unchanged diester forms themselves may have biological activity. Linoleic acid in the form of 1,3-diglyceride has been found to have anti-cancer effects that were selective on cancer but not normal cells and which were not observed with other forms of linoleic acid [A. Matsuzaki et al., Cancer Res., 49, 5702-5707 (1989)]. It is possible that this and possibly other effects require the addition of two fatty acid molecules arranged as in the case of 1,3-diglyceride. A similar arrangement will be achieved with 1,3-propanediol, and therefore intravenous administration of certain propanediol derivatives, which will ensure that the diol form will circulate for some time before its complete metabolism, may be particularly valuable.

Fatty acids have a number of desirable biological and therapeutic activities, which have been described in detail in a number of publications by the inventors and others. Four of these fatty acids, GLA, DGLA, SA and EPA, are involved in a wider spectrum of effects, including:

Cardiovascular activity including vasodilation, lowering of blood pressure, inhibiting platelet aggregation, lowering triglyceride and LDL-cholesterol levels, increasing HDL-cholesterol levels, and inhibiting smooth muscle proliferation.

2. Anti-inflammatory activity including reduction of pro-inflammatory mediators such as cytokines and arachidonic acid-derived icosanoids, reduction of neutrophil migration and neutrophil respiratory aggregation, reduction of local inflammatory response, inhibition of inflammation in various animal models such as uric acid-induced inflammation and associated arthritis arthritis) and treatment of various inflammatory disorders such as osteoarthritis and rheumatoid arthritis.

3. Immunomodulatory function involving the reduction of the respective immune and allergic responses in animal models such as experimental allergic encephalomyelitis and uveitis, bronchial and skin hyperactivity in hypersensitive animals, leading to the concept that they are valuable in human diseases where an excessive immune response is involved.

4. A respiratory effect comprising bronchodilation and inhibition of bronchoconstrictor activity.

5. Improving calcium balance by increasing calcium absorption, reducing calcium excretion, improving calcium deposition in bone, and reducing ectopic calcium deposition in tissues such as arteries and kidneys.

6. Anti-cancer effects of triple species, selective cytotoxic damage and induction of apoptosis in cancer cells but not normal cells, inhibition of growth by reducing the activity of growth factors and interfering with secondary mesenger systems required for growth, inhibiting metastasis by various activities including E-cadcrine expression and inhibition proteolytic enzymes such as urokinases, lipoxygenases and matrix metalloproteinases; and inhibition of cancer-related cachexia.

7. Treatment of nerve cells comprising maintenance of normal neural membrane structures and functions and normal pre- and post-synaptic neurotransmitter activities.

These desirable activities mean that this group of fatty acids can be used to treat many different disorders including cardiovascular disorders of many types, inflammatory disorders including rheumatoid arthritis, osteoarthritis, ulcerative colitis and Crohn's disease, respiratory disorders including asthma, mental disorders including schizophrenia, alcohol, schizophrenia, alcohol, concentration disorders, depression and Alzheimer's disease, neurological disorders including multiple sclerosis and Huntington's chorea, renal and urinary tract disorders including various types of renal inflammatory disease and urinary calculi, metabolic disorders including osteoporosis and ectopic calcification and gastrointestinal ulcer and gastrointestinal ulcer diseases. Although conjugated linoleic acid (cLA) has not been as widely tested as, say, GLA or EPA, it also appears to have a wide range of actions including effects valuable in the treatment of cancer, cardiovascular and metabolic diseases.

GLA, DGLA, AA and columbinic acid have desirable effects on the skin and are particularly valuable in the treatment of skin diseases such as atopic eczema, psoriasis, urticaria and allergic reactions.

AA is often considered a potentially harmful fatty acid. However, it is an essential component of all normal cell membranes and has been found to be present at low concentrations in various diseases including atopic eczema, schizophrenia [Horrobin et al., Schizophrenina Res., 13, 195-207 (1994)] and cardiovascular disorders ([Horrobin , Prostaglandins Leukotr, EFAs 53, 385-396 (1995)] AA is probably particularly valuable in these situations and also in other psychiatric disorders such as alcoholism and concentration disorders, where concentrations are also often low.

DHA also has some of the aforementioned effects of EFA, but is found mainly in large quantities in cell membranes and in particular in the membranes of the heart, retina and brain. DHA also has a pronounced anti-inflammatory and desirable cardiovascular effect. DHA is likely to be particularly valuable in cardiovascular, retinal and visual disorders including retinitis pigmentosa, senile macular degeneration and dyslexia, and mental and neurological disorders including schizophrenia, concentration disorders, depression, alcoholism, and other forms of Alzheimer's disease multiple sclerosis.

Recently it has also been found that infections are likely to respond to fatty acids, particularly GLA and DGLA, EPA and DHA. Many bacteria, including strains that are highly resistant to antibiotics, are killed by these fatty acids. Recent laboratory work has also shown that these highly unsaturated fatty acids are also important in successful responses to diseases such as malaria and protozoal diseases.

It is therefore apparent that various specific fatty acids are likely to deliver efficacy to drugs and other biologically active substances of almost any class in both treatment, disease prevention, skin care and nutrition, as well as having valuable therapeutic effects when administered in a medicinal product. diol form as individual fatty acids or as two different fatty acids in the same molecule. Of particular value in therapy is that under most circumstances fatty acids are highly non-toxic and can be administered safely in large doses without the risk of major side effects.

As a specific example of the therapeutic efficacy of diesters, a 1,3-GLA-EPA propanediol diester has been tested in the treatment of ASPC-1 human pancreatic cancer transplanted subcutaneously into nude mice that are able to receive foreign transplant due to loss of thymus function without rejection. Each of the 15 mice was injected subcutaneously with 5 million ASPC-1 cells suspended in Matrigel and DMEM buffer. All animals developed a tumor, its size could be measured using a caliper, and its volume could be estimated from the average. Tumor size for each animal was measured twice weekly for five weeks. The animals were divided into three groups. Five animals were used as a control and received only 10 g / kg corn oil per day, but additionally received two injections per week at a dose of 1.5 g / kg GLA-EPA diester. The diester was administered as a 20% emulsion in which 2% oat galactolipid was used as an emulsifier; the intravenous emulsion was very well tolerated and did not cause any hemolysis or thrombophlebitis, or any other form of anxiety in the animals. The remaining 5 animals received 10 g / kg / day of GLA-EPA diester instead of corn oil. Treatment was continued for three weeks and then tumors were allowed to grow for a further two weeks, after which the animals were sacrificed and the tumors were removed and their weights were determined. The average tumor weight was: control group 1240 ± 290 mg; intravenous GLA-EPA group 820 ± 180 mg; GLA-EPA oral administration group 490 ± 160. Thus, tumor growth was substantially inhibited by both oral and intravenous administration of GLA-EPA diester without causing any side effects or anxiety conditions of the animals. This demonstrates that the GLA-EPA diester can be effectively used in the treatment of cancer as predicted from the effects of GLA and EPA administered separately that are capable of selectively destroying human cancer cells in laboratory cultures. Diesters are thus biologically active by the administration of various fatty acids. It is therefore logical to assume that diesters have many of the desirable effects of fatty acids that have been mentioned in many publications in the literature (e.g., DF Horrobin, eds., Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine: Wiley-Liss, New York, 1990; AP Simopoulos et al., Ed., Health Effects of Omega-3 Polyunsaturated Fatty Acids in Seafoods, Karger, Basel, 1991; Fats and Oils in Human Nutrition, World Health Organization, Rome, 1994; Unsaturated Fatty Acids: Nutritional and the Physiological Significance (British Nutrition Foundation, Chapman and Hall, London, 1992).

Specific use of specific 1,3-propanediol compounds

1. 1,3-Propanediol as derivatives containing: two fatty acids in which one fatty acid is GLA or DGLA and the other is GLA, DGLA, SA, EPA, DHA, cLA (conjugated linoleic acid) or CA (columbinic acid) per treatment:

(a) complications of diabetes, in particular neuropathy and retinopathy; and improving insulin responses in diabetes and pre-diabetes;

b) cancers;

c) osteoarthritis;

d) rheumatoid arthritis;

(e) other inflammatory or autoimmune diseases including Sjogren's syndrome, systemic lupus, ulcerative colitis, Crohn's disease and uveitis;

(f) respiratory diseases including asthma;

(g) neurological disorders including multiple sclerosis, Parkinson's disease and Huntington's chorea;

(h) renal and urinary disorders;

(i) cardiovascular diseases;

(j) dcgenerative eye diseases including retinitis pigmentosa and senile macular degeneration;

(k) mental illnesses, including schizophrenia, Alzheimer's, concentration disorders, alcoholism and depression;

l) prostatic hypertrophy and prostatitis;

(m) impotence and male infertility;

n) mastalgia;

o) male baldness;

p) osteoporosis;

(q) dermatological disorders, including atopic eczema, hand eczema, psoriasis, urticaria and allergic disorders;

(r) dyslexia and other learning disabilities;

s) cancer cachexia.

2. 1,3-Propanediol as a derivative containing two fatty acids in which one fatty acid is AA and the other is AA, GLA, DHA, DGLA or EPA for the treatment of disorders as referred to in (1) and in particular a), g) , i), j), k), q), and ar).

3. 1,3-Propanediol as a derivative containing two fatty acids in which one is EPA and the other is EPA or DHA for the treatment of any disorder as mentioned in (1), but especially for (b), (c), (d); e), f), g), h), i), j), k), p), r) and s).

4. 1,3-Propanediol as a derivative in which one position is occupied by a fatty acid selected from GLA, DGLA, AA,

SA, cLA, EPA or DHA and the second position is taken by a composition selected from the following list, whose chemical structure is such that it can be linked to 1,3-propanediol by one or more of the bonds described herein:

(a) tryptophan for the treatment of any disease, but in particular for psychological or neurological disorders, behavioral disorders, pain and in particular depression, sleep disorders and migraine;

(b) phenylalanine for the treatment of any disease, but in particular depression, multiple sclerosis and chronic fatigue syndrome;

(c) arginine for the treatment of any disease but in particular of diseases in which nitric oxide production is detectable;

(d) carnitine or carnitine derivatives for the treatment of any disease, but in particular muscle weakness, cardiac weakness, chronic fatigue syndrome, Alzheimer's disease and peripheral neuropathy;

(e) any other amino acid or related substance for the treatment of any disease or aminolevulonic acid, or a derivative thereof for the treatment of any disease, but in particular of cancers;

(f) adenyl succinate or related substances for the treatment of any disease, but in particular muscular dystrophy, cardiac weakness, chronic fatigue, Alzheimer's disease and other dementias;

(g) aspirin, salicylic acid, indomctacin, ibuprofen or any other non-steroidal anti-inflammatory drug for the treatment of any disease, but in particular inflammatory disorders or pain, Alzheimer's disease and other dementias, and any disease in which platelet aggregation should be inhibited;

(h) any antibiotic for the treatment of any relevant infectious disease, but in particular tetracycline, clindamycin, minocycline, chlorotetracycline and erythromycin for the treatment of acne;

(i) any malaria or antiprotozoal drug for the treatment of any disease, but in particular chloroquine, mepacrine, quinacrine and mefloquine for the treatment of malaria, protozoal disorders, inflammatory disorders and schizophrenia;

j) any antifungal drug for the treatment of any disease, but in particular meronidazole, antifungal imidazoles, nitroimidazoles and amphotericin for the treatment of fungal infections of various types;

(k) any anti-inflammatory steroid for the treatment of any disease, but in particular hydrocortisone and betamethasone for the treatment of skin disorders and beclomethasone and budesonide for the treatment of asthma;

(l) any gonadal steroid for the treatment of any disease, but in particular estrogens and progestogens for the treatment of ovarian deficiency and osteoporosis and androgens for the treatment of testicular insufficiency;

m) any adrenal steroid for the treatment of any disease, but especially dehydroepiandrosterone for the treatment of aging-related disorders;

(n) any retinoid for the treatment of any disease, but in particular tretinoin and isotretinoin for the treatment of dermatological disorders and for use in skin care;

o) any anticancer drug for the treatment of cancer;

p) any antipsychotic drug for the treatment of schizophrenia and other psychoses;

q) any antidepressant drug for the treatment of any disease, but especially for the treatment of depression;

(r) any anti-anxiety medicine for the treatment of any disease, but in particular for the treatment of anxiety and panic fear;

(s) any immunosuppressive drug for the treatment of any disease, but in particular cyclosporine and tacrolimus for the control of immunity following organ transplantation and for the treatment of autoimmune and inflammatory disorders including psoriasis, eczema, asthma, rheumatoid arthritis and inflammatory bowel diseases;

(t) any proton pump inhibitor or H2 antagonist for the treatment of any disease, but in particular diseases associated with excessive gastric acid production or reduced gastric acid defense;

(u) any diuretic for any disease, but in particular for diseases associated with fluid retention and hypertension;

(v) any calcium antagonist used for any disease but in particular for cardiovascular disease;

(w) any angiotensin converting enzyme inhibitor or angiotensin antagonist used for any disease but in particular for cardiovascular diseases;

(x) any β-blocker used for any disease but in particular for cardiovascular disorders;

y) any antiepileptic drug used for any disease, but especially phenytoin, carbamazepine, valproate, etosuximide, vigabatrin or lamotrigine for the treatment of epilepsy;

z) any hypolipidemic agent for the treatment of any disease, but particularly fibrates and statins used to lower cholesterol and modify cholesterol;

(aa) any oral hypoglycaemic or insulin sensitizing agent used to treat diabetes;

(bb) any bisphosphonates used in the treatment of osteoporosis, Paget's disease or cancer;

(cc) any contrast agent used in radiology, including diatrizoate compounds, iodipamide, ioglycamates, iopanoates, iofendylate, iotalamate, ioxaglat, metrizamide and related compounds;

dd) any peptide or protein for use in the treatment of diseases for which the peptides or proteins themselves are suitable, including insulin, calcitonin, erythropoietin, and other peptides;

(ee) any vitamin used in the treatment of any disease or used in foods, nutritional products or food ingredients as a way of effectively providing vitamins;

(ff) any antioxidant used in the treatment of any disease, but in particular those in which antioxidants may be particularly useful, including cardiovascular diseases, cancer and inflammatory disorders, and any antioxidant used as a food or preservative or as an ingredient in food, a food additive or nutritional supplement;

(gg) any medicament based on porphyrin or bacteriochlorin, in particular their tetrakis (hydroxyphenyl) derivatives, used in the photodynamic therapy of cancers.

Facilitate synthesis

The preferred uses of 1,3-propanediol in comparison with triglycerides in particular will be discussed below.

In particular, it is proposed that 1,3-propanediol be used instead of glycerol in the esterification of fatty acids, especially where only one type of fatty acid (for example τ-linoleic acid) is to be attached to a 3-carbon "backbone" chain. Although the diesters are chemically very similar, diesters can be produced under very mild conditions and within a few hours. Either harsh conditions or fatty acid chlorides must be used to produce triglycerides, or biocatalysts (which require a reaction time of several days) are required.

Methods for the synthesis of triglycerides can be summarized as follows: chemical reaction with metals, metal chlorides or organic acids as catalysts; the use of fatty acid chlorides; use of immobilized enzymes.

All processes using acids, metals or metal chlorides as catalysts are very similar and have common advantages and disadvantages. Many problems are related to methods, i.e., acidic conditions and high temperatures (140-180 ° C). The p-TSA method is likely to have the least problems, and is carried out under the slightest conditions (140 ° C). The reaction of glycerol with fatty acid chlorides is carried out under "cold" conditions, but toxic gases are released and the reaction may spiral out of control unless closely monitored. The method also has the disadvantage that the fatty acid chlorides themselves must be produced first; this additional step reduces the overall efficiency of the process. A particular class of enzymes, lipases, can be used to catalyze the esterification reaction under very mild conditions (e.g. at 60 ° C) and these catalysts are likely to be selected when polyunsaturated fatty acids are used. However, most enzymes interact most efficiently with positions 1 and 3 of glycerol. The attachment of the fatty acid to position 2 is slow and often dependent on "acyl migration", that is, the fatty acid must first be attached to position 1 or 3 and then migrates to position 2 where it remains attached. Thus, the enzymes catalyzed by gout enzymes are required for the quantitative reaction to proceed.

Theoretically, the methods of esterifying 1,3-propanediol can be applied to the same methods as used in glycerol. However, considering that enzymes first catalyze the attachment of fatty acids to positions 1 and 3 of glycerol, it is clear that they will be particularly effective for the production of diesters. In fact, this is the case where reactions can be completed in a few hours at temperatures that are even lower (e.g., 45 to 60 ° C) than those required for triglyceride synthesis. After four hours, free fatty acid may no longer be present, and after eight hours, the diester yield may reach 95%, equilibrating with the monoester.

Another complication in the synthesis of specific triglycerides is the presence of both primary and secondary hydroxyl groups and the prochiral center at the central carbon atom of glycerol. These problems can be solved by using carefully selected protecting groups and by chiral synthesis. However, this results in multi-step synthesis with decreasing yield and increasing impurity concentrations at each step. In contrast, 1,3-propanediol has only primary hydroxyl groups and no prochiral centers. As a result, the synthesis is reduced to a maximum of two steps with improved overall yield and reduced impurity levels.

In summary, the reaction to produce diesters from polyunsaturated fatty acids and 1,3-propanediol is faster and can be performed under much milder conditions than the corresponding triglyceride syntheses. This leads to a more economical and less harmful production method and minimizes the risk that the reactants or products will change or be degraded during processing.

composition

The compounds can be made by any suitable method known to those skilled in the art of preparing pharmaceutical, skin care or food preparations. They can be administered orally, enterally, topically, parenterally (subcutaneously, intramuscularly)

(Rectal, vaginal or any other suitable route).

Like triglycerides, 1,3-propanediol diesters, especially those containing two fatty acids, can be easily emulsified using phospholipid or especially galactoipid emulsifiers. Such emulsions are particularly suitable for administration by the oral, enteral and intravenous routes.

For example, fatty acid diesters (UFAs) occur as free-flowing oils and can therefore be formulated as follows:

1. Preparation of a 20% emulsion of diesters of GLA and EPA with 1,3-propanediol

Oral emulsions were prepared by high pressure homogenization. The particle size distribution and the zeta potential of the resulting emulsions were determined by dynamic light scattering at room temperature. Particle size measurements were performed at room temperature (Zetasizer 4 Malvem Instruments Limited).

An oil-in-water emulsion (200 g batch) was produced, containing the following components:

component % emulsifier (galactolipid) * 2.00 Diester (GLA-EPA) 20.00 ascorbyl palmitate (AP) 0.02 Vitamin E 0.5 Water do 100,00

* Scotia Lipid Teknik's patent entitled "Oil-in-water emulsions"

PCT / SE95 / 00115 (WO 95/20943)

The galactolipid emulsifier was dispersed in the diester and the vitamin E, AP and water were mixed. The oil phase was added to the aqueous phase under high shear conditions (Ultraturrax) at a rate of 4, over several minutes. This preemulsion was then homogenized at 80 MPa and 50 ° C for six cycles (min-Lab 8.30 H; APV Rannie AS, Denmark). The emulsion formed had an average droplet size of 230 nm.

Antimicrobial preservatives - potassium sorbate and flavoring agents may be added to the oral emulsion.

2. Preparation of an intravenous 20% emulsion of diester GLA and EPA with 1,3-propanediol

In a similar manner, 200 g of an oil-in-water emulsion was prepared containing the following components:

ingredients % emulsifier 2.00 Diester (GLA-EPA) 20.00 glycerol 2.0 Water do 100,00

Said emulsion, homogenized for 6 minutes in a high pressure homogenizer, had an average droplet size of 211 nm and a zeta potential - 40 mV. These i. in. the emulsions may be further filtered through a 0.22 micron pore size membrane or may be autoclaved to change the droplet size.

Dosages of the active compounds for administration may range from 1 mg to 200 g per day, preferably from 10 mg to 10 g and very preferably from 10 mg to 3 g, depending on its kind. In the treatment of cancer, doses ranging from 2 to 150 g / day may be preferred. They can be administered topically, where appropriate, wherein the active ingredients comprise from 0.001% to 50% of the topical preparation, preferably from 0.05% to 20%, and particularly preferably from 0.1% to 10%.

DETAILED DESCRIPTION OF THE INVENTION

Illustrative examples of fatty acid-associated NSAIDs are disclosed in EPA-0 675 103, previously mentioned. Illustrative syntheses of the linkage of fatty acids through the 1,3-propanediol moiety follow along with other generally illustrative materials.

Example 1

1,3- (Di-z, z, z-octadeca-6,9,12-trienoyloxy) propane (Diester GLA with 1,3-propanediol)

A solution of 1,3-dicyclohexylcarbodiimide (1.07 g) and 4- (N, N-dimethylamino) pyridine (0.59 g) in methylene chloride (5 mL) was added to a solution of 1,3-dihydroxypropane (0.152 mL), z, z-octadeca-6,9,12-trienic acid (95%, 1.36 g) in methylene chloride (15 mL). The reaction mixture was stirred at room temperature under nitrogen until the reaction was complete as determined by thin layer chromatography. Hexane (80 mL) was added to the reaction mixture. The precipitate was removed by filtration and washed thoroughly with hexane. The combined filtrates were evaporated and purified by flash chromatography to give 1,3- (di-z, z, z-octadeca-6,9,12-trienoyloxy) propane as a pale yellow free-flowing oil.

Example 2 1- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (z-octadeca-9-enoyloxy) propane (diester of GLA and oleic acid with 1,3-propanediol)

Part 1

A solution of z, z, z-octadeca-6,9,12-trienic acid (150 g) in methylene chloride (500 mL) was added dropwise to a mixture of 1,3-dihydroxypropane (205 g), 1,3-dicyclohexylcarbodiide (130 g) and 4- (N, N-dimethylamino) pyridine (87 g) in methylene chloride (2500 mL) at room temperature under nitrogen. When thin layer chromatography showed that the reaction was complete, the reaction mixture was filtered. The filtrate was washed with dilute hydrochloric acid, water and saturated sodium chloride solution. The solution was dried, evaporated and purified by dry column chromatography to give 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane as a pale yellow oil.

Part 2

A solution of 1,3-dicyclohexylcarbodiimide (23.7 g) and 4- (N, N-dimethylamino) pyridine (15.9 g) in methylene chloride (200 mL) was added to a solution of 1- (z, z, z-octadeca- 6,9,12-trienoyloxy) -3-hydroxypropane (33.6 g) and z-octadeca-9-enoic acid (30 g) in methylene chloride (400 mL) under nitrogen at room temperature. After reaction as shown by thin layer chromatography analysis, the solution was diluted with hexane, filtered, evaporated and purified by dry column chromatography to give 1- (z, z, z-octadea-6,9,12-trienoyloxy) -3- (z-octadeca-9-enoyloxy) propane as a free-flowing pale yellow oil.

Example 3 1- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (z, z, z, z, z-icoza-5,8,11,14,17-pentenoxyoxy) ) Propane (diester of GLA and EPA with 1,3-propanediol)

Prepared as in Example 2, Part 2, wherein the z-octadeca-9-enoic acid was replaced with z, z, z, z, z-icoza-5,8,11,14,17-pentenoic acid. Chromatography gave 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3- (z, z, z, z, z-icoza-5,8, -

II, 14,17-pentenoyloxy] propane as a pale yellow oil.

Example 4 1,3-Di (z, z, z-octadeca-6,9,12-trienoyloxy) propane (1,3-propanediol GLA diester)

Prepared as in Example 2, Part 2, except that z-octadeca-9-enoic acid was replaced with z, z, octadeca-6,9,12-trienic acid. Chromatography gave 1,3-di (z, z, z-octadeca-6,9,12-trienoyloxy) propane as a pale yellow oil.

Example 5 (±) -1- (1,2-Dithiolane-3-pentanoyloxy) -3- (z, z, z-octadeca-6,9,12-trienoyloxy) propane (diester of lipoic acid and GLA of 1.3 propanediol)

A mixture of 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) and 4- (N, N-dimethylamino) pyridine (480 mg, 3.98 mmol) in tert-butyl methyl ether (15 mL) was added to the lipoic acid mixture (645 mg, 3.12 mmol) and 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1g, 3 mmol) in tert-butyl methyl ether (30 mL). The mixture was stirred at room temperature under nitrogen for 5 hours, the progress of the reaction was monitored by thin layer chromatography (40% ethyl acetate / hexane). After completion of the reaction, the mixture was filtered, evaporated and purified by flash chromatography (hexane, 2% ethyl acetate / hexane, 5% ethyl acetate / hexane and finally 10% ethyl acetate / hexane) to give (±) -1- (1,2-). dithiolane-3-pentanoyloxy) -3- (z, z, z-octadeca-6,9,12-trienoyloxy) propane as a viscous yellow oil.

Example 6 1 - [[Z] -5-Fluoro-2-methyl-1- [4- (methylsulfinyl) benzylidene] -indene-3-acetyloxy] -3- (z, z, z-octadeca-6.9, 12-trienoyloxy) propane (diester of sulindac and GLA with 1,3-propanediol)

A solution of 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) in tert-butyl methyl ether (30 mL) was added to a mixture of sulindac (1.12 g, 3.15 mmol), 4- (N, N-dimethylamino) pyridine (480 mg, 3.9 mmol) and 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1 g, 3 mmol) in tert-butyl methyl ether (15 mL) . The mixture was stirred at room temperature under nitrogen for 5 hours, the progress of the reaction was monitored by thin layer chromatography (40% ethyl acetate / hexane). Upon completion, the mixture was filtered, evaporated and purified by flash chromatography (40% acetate / hexane, then 50% ethyl acetate / hexane and finally 60% ethyl acetate / hexane) to afford 1 - [[Z] -5-fluoro-2]. methyl 1 / 4- (methylsulfinyl) benzylidene / indene-3-acetyloxy] -3- (z, z-octadeca-6,9,12-trienoyloxy) propane as a waxy yellow solid.

Example 7 1 - [[R] -3-Acetoxy-4- (trimethylammonio) butyroyloxy] -3- (z, z, z-octadeca-6,9,12-trienoyloxy) propane (diester of acetylcamitin and GLA with 1 , 3-propanediol)

Freshly distilled thionyl chloride (1.5 mL) was slowly added to (R) -acetylcamitin (1 g) in a pear shaped flask. Care was taken to keep the reagents at the bottom of the flask until a clear solution was obtained. After 4 hours at room temperature, the remainder of the thionyl chloride was removed under reduced pressure (maintaining the temperature in the flask less than 30 ° C). This gave the acid chloride as a highly hygroscopic white solid which was used immediately without further purification. To the flask was added 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1.4 g, 4.17 mmol) and dry tetrahydrofuran (4 mL). The mixture was left at room temperature overnight. TLC analysis (40% ethyl acetate / hexane) showed that the reaction was complete. The reaction mixture was added dropwise to hexane (250 mL) with vigorous stirring. A fine off-white precipitate formed and was collected by centrifugation. After removal of the supernatant, the solid was resuspended in hexane and centrifuged. The hexane wash procedure was repeated once more to give 1 - [[R] -3-acetoxy-4- (trimethylammonio) butyroyloxy] -3- (z, z, z-octadeca-6,9,12-trienoyloxy) propane .

Example 8 1- [3,3-Dimethyl-7-oxo-6 - [(phenoxyacetyl) amino] -4-thia-1-azabicyclo [3.2.0] heptan-2-oyloxy] -3- (z, z, z-octadeca-6,9,12-trienoyloxy] propane (diester of penicillin V and GLA with 1,3-propanediol)

A mixture of penicillin V (1 g, 2.9 mmol), 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (860 mg, 2.6 mmol),

1,3-dicyclohexylcarbodiimide (620 mg, 3 mmol) and 4- (N, N-dimethylaminopyridine (catalytic) in dichloromethane (30 mL) were stirred at room temperature overnight The reaction mixture was diluted with hexane (50 mL), filtered The residue was washed with hexane (3 x 50 mL) to remove unreacted 1- (ζ, ζ, ζ-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane, and the semi-solid residue was dissolved in diethyl ether ( 150 ml), washed with water (100 ml) and dried, the ether solution was diluted with hexane (125 ml), and the solution was filtered through a pad of silica (4 cm x 4 cm), and the filtrate was evaporated to give 1- [3, m.p. 3-dimethyl-7-oxo-6 - / (phenoxyacetyl) amino / -4-thia-l-azabicyclo [3.2.0] heptan-2-oyloxy] -3- (z, z, z-octadeca-6 (9,12-trienoyloxy) propane as a viscous colorless oil.

Example 9

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-indole-3-acetyloxy] propane (indomethacin diester and GLA) with 1,3-propanediol)

A solution of 1,3-dicyclohexylcarbodiimide (58 g, 0.28 mol and 4- (N, N-dimethylamino) pyridine (37.9 g, 0.31 mol) in methylene chloride (800 mL) was added to the 1- (z, z, z-octadeca-6,9,12-tricnoyloxy) -3-hydroxypropane (79.5 g, 0.24 mol) and indomethacin (93.2 g, 0.26 mol) in methylene chloride (400 mL) Stirring was continued for 3 hours The mixture was filtered, evaporated and purified by dry column chromatography (ethyl acetate / hexane) The product fractions were collected and concentrated to afford 1- (ζ, ζ, ζ-). octadeca-6,9,12-trienoyloxy) -3- [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-indole-3-acetyloxy] propane as a light yellow viscous oil.

Example 10 1- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (2-pyrrolidinecarboxy) propane (diester of proline and GLA with 1,3-propanediol)

Part 1

A solution of 1,3-dicyclohexalecarbodiimide (674 mg, 3.3 mmol) and 4- (N, N-dimethylamino) pyridine (472 mg, 3.9 mmol) in methylene chloride (20 mL) was added to a solution of 1- ( z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1 g, 2.97 mmol) and N-tBOC-proline (671 mg, 3.12 mmol) in methylene chloride (20 mL) at room temperature and under nitrogen Stirring was continued for 7 hours and the mixture was stored overnight at 0 ° C. The mixture was filtered and purified by column chromatography (methanol / methylene chloride) to give 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3- (N-tBOC-2-pyrrolidinecarboxy) propane as yellow oil.

Part 2

The protected product was dissolved in a 10% (v / v) mixture of anisole and trifluoroacetic acid (10 mL) and left

At room temperature under nitrogen for 30 minutes. After TLC analysis showed complete deprotection, the mixture was purified by column chromatography (8% methanol, 42% methylene chloride and 50% ethyl acetate) to afford 1- (z, z, z-octadeca-). 6,9,12-trienoyloxy) -3- (2-pyrrolidinecarboxy) propane as a viscous orange oil.

Example 11

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (2-amino-3-indolylpropanoyloxy) propane (tryptophan and GLA diester with 1,3-propanediol)

Part 1

A solution of 1,3-dicyclohexylcarbodiimide (674mg, 3.3 mmol) and 4- (N, N-dimethylamino) pyridine (472 mg, 3.9 mmol) in methylene chloride (20 mL) was added with stirring to a solution of 1- (z z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1 g, 2.97 mmol) and N-tBOC-tryptophan (950 mg, 3.12 mmol) in methylene chloride (20 mL) at at room temperature and under nitrogen. Stirring was continued for 7 hours and the mixture was stored overnight at 0 ° C. The mixture was filtered and purified by column chromatography (methanol / methylene chloride) to give 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3- (N-tBOC-2-amino-3-indoylpropanoyloxy). ) propane as a yellow oil.

Part 2

The protected product was dissolved in a 10% (v / v) mixture of anisole and trifluoroacetic acid (6.1 mL) and left at room temperature under nitrogen for 15 minutes. After TLC analysis showed complete deprotection, the mixture was purified by column chromatography (8% methanol, 42% methylene chloride and 50% ethyl acetate) to afford 1- (z, z, z-octadeca-). 6,9,12-trienoyloxy) -3- (2-amino-3-indolylpropanoyloxy) propane as a viscous red wax.

Example 12

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (α-amino-3-phenyl-propionyloxy) propane (phenylalanine diester and 1,3-propanediol GLA)

Part 1

A solution of 1,3-dicyclohexylcarbodiimide (1.77 g, 8.57 mmol) and 4- (N, N-dimethylamino) pyridine (1.24 g, 10.13 mmol) in methylene chloride (30 mL) was added with stirring to a solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (2.62 g, 7.79 mmol) and N-tBOC-phenylalanine (2.17 g, 8.18 mmol) in methylene chloride (30 mL) at room temperature and under nitrogen. Stirring was continued for 7 hours and the mixture was stored overnight at 0 ° C. The mixture was filtered and purified by column chromatography (methanol / methylene chloride) to give 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3- (N-tBOC-α-amino-3-phenylpropionyloxy) ) propane as a yellow oil.

Part 2

The protected product was dissolved in a 10% (v / v) mixture of anisole and trifluoroacetic acid (17 mL) and left at room temperature under nitrogen for 30 minutes. After thin layer chromatography analysis showed complete deprotection, the mixture was purified by column chromatography (8% methanol, 42% methylene chloride and 50% ethyl acetate) to give 1- (z, z, z-octadeca-6, 9,12-Tricnoyloxy) -3- (α-amino-β-phenyl-propionyloxy) propane as a viscous yellow oil.

Example 13

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (4-aminobutanoyloxy) propane (diester of GABA and GLA with 1,3-propanediol)

Part 1

A solution of 1,3-dicycohexylcarbodiimide (0.84 g, 4.06 mmol) and 4- (N, N-dimethylamino) pyridine (0.59 mg, 4.79 mmol) in methylene chloride (10 mL) was added with stirring to a solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1.24 g, 3.69 mmol) and N-tBOC-GABA (0.75 g, 3.69) mmol) in methylene chloride (15 mL) at room temperature and under nitrogen. Stirring was continued for 7 hours and the mixture was stored overnight at 0 ° C. The mixture was filtered and purified by column chromatography (ethyl acetate / hexane) to give 1- (z, z, z-octadeca-6,9,1,2-trienoyloxy) -3- (N-tBOC-4-aminobutanoyloxy) propane as colorless oil.

Part 2

The protected product was dissolved in a 10% (v / v) mixture of anis and trifluoroacetic acid (10.5 ml) and left at room temperature under nitrogen for 30 minutes. After thin layer chromatography analysis showed that the deprotection was complete, the mixture was purified by column chromatography (8% methanol, 42% methylene chloride and 50% ethyl acetate) to afford 1- (z, z, z-octadeca-). 6,9,12-trienoyloxy) -3- (4-aminobutanoyloxy) propane as a yellow oil.

Example 14 3,3'-Thiodi- [1-propionyloxy- [3- (z, z, z-octadeca-6,9,12-trienoyloxy) propane]] (GLA bis-diester and 1,3-propanediol with 3,3 '-thiodipropionic acid)

A solution of 1,3-dicyclohexylcarbodiimide (660 mg, 3.22 mmol) and 4- (N, N-dimethylamino) pyridine (445 mg, 3.64 mmol) in methylene chloride (10 mL) was added with stirring to a solution of 1- ( z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (940 mg, 2.8 mmol) and 3,3'-thiodipropionic acid (250 mg, 1.4 mmol) in methylene chloride (30 ml) at room temperature and under nitrogen. Stirring was continued for 4 hours. The mixture was diluted with hexane (50 mL) filtered, evaporated and purified by chromatography (ethyl acetate / hexane). The product fractions were collected and evaporated to give 3,3'-thiodo- [1-propionyloxy- [3- (z, z, z-octadeca-6,9,12-trienoyloxy) -propane]] as a colorless oil.

Example 15

- [1- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3-propyl] -4- (z, z, z-octadeca-6,9,12-trienyl) butane -1 , 4-dioate [diester (monoester of GLA with 1,3-propanediol) and GLA alcohol with succinic acid]

Part 1

A mixture of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (10 g, 30 mmol) and succinic anhydride (3 g, 30 mmol) in dry tetrahydrofuran (100 mL) was added. The mixture was stirred at room temperature until a clear solution was obtained. This solution was cooled to 0 ° C and a solution of 1,8-diazabicyclo [5.4.0] undec-7-ene (4.5 mL, 30 mmol) in dry tetrahydrofuran (50 mL) was added dropwise. After 3 hours, thin layer chromatography indicated that most of the monoester had reacted. A few crystals of succinic anhydride were added and stirring was continued for another 30 minutes. The reaction mixture was diluted with diethyl ether (250 mL) and washed with 2M hydrochloric acid (2 x 250 mL), water (250 mL) and brine (250 mL). It was then dried (sodium sulfate) and evaporated to dryness. The material was used without any further purification.

Part 2

Oxalyl chloride (3.9 mL, 45 mmol) was added to a solution of the product of Part 1 (13 g, 30 mmol) in methylene chloride (75 mL). The mixture was stirred at room temperature under nitrogen for 2 hours and evaporated to dryness. Hexane (75 mL) was added and the mixture was re-evaporated to dryness. This process was repeated with two additional portions of hexane (about 75 mL each). The material was used without any further purification.

Part 3

The acid chloride solution prepared in Part 2 (1 g,

2.2 mmol) in methylene chloride (10 mL) was added dropwise to a solution of z, z, z-octadeca-6,9,12-trienol (635 mg,

2.4 mmol), triethylamine (1 mL, 7.2 mmol) and 4- (N, N-dimethylamino) pyridine (catalytic amount) in methylene chloride (20 mL) at room temperature. After completion of the reaction, the mixture was evaporated and purified by flash chromatography (ethyl acetate / hexane) to give 1- (1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-propyl) -4- (z, z, z-octadeca-6,9,12-trienyl) butane-1,4-dioate as a colorless oil.

Example 16 1- (2,3,5-Triiodobenzoyloxy) -3- (z, z, z-octadeca-6,9,12-trienoyloxy) propane (2,3,5-triiodobenzoic acid diester and GLA with 1,3-propanediol) )

2,3,5-Triiodobenzoyl chloride (1.54 g, 3.08 mmol) was added to a mixture of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1 g, 2 , 97 mmol) and triethylamine (1 mL) in methylene chloride (80 mL) and the resulting mixture was stirred under nitrogen at room temperature overnight. The mixture was evaporated and purified by flash chromatography (ethyl acetate / hexane) to give 1- (2,3,5-triiodobenzoyloxy) -3- (z, z, z-octadeca-6,9,12-trienoyloxy) propane.

Example 17 (+) - 1- (1,2-Dithiolane-3-pentanoyloxy) -3 - (z, z, z, z, z, z-docoza-4,7,10,13,16,19-hexenoyloxy ) Propane (diester of DHA and lipoic acid with 1,3-propanediol)

Part 1

A solution of z, z, z, z, z, z-docoza-4,7,10,13,16,19-hexenoic acid (6.4 g, 19.5 mmol) in methylene chloride (225 mL) was added dropwise to a solution of 1,3-propanediol (7.5 g, 99 mmol), 1,3-dicyclohexylcarbodiimide (4.5 g, 20 mmol) and 4- (N, N-dimethylamino) pyridine (2.1 g, 17 mmol) ) in methylene chloride (225 mL) at -10 ° C. The reaction mixture was stirred overnight and warmed to room temperature. The reaction mixture was filtered, evaporated and purified by flash chromatography (ethyl acetate / hexane) to give 1- (z, z, z, z, z, z-docoza-4,7,10,13,16,19-hexenoyloxy) -3-hydroxypropane as a light yellow oil.

Part 2

A solution of 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) and 4- (N, N-dimethylamino) pyridine (480 mg, 3.9 mmol) in methylene chloride (30 mL) was added to a mixture of 1- (z, z, z, z, z, z-docoza-4,7,10,13,16,19-hexenoyloxy) -3-hydroxypropane (1.16 g, 3 mmol) and lipoic acid (645 mg, 3.12 mmol) ) and methylene chloride (15 mL). After 2.5 hours at room temperature under nitrogen, the mixture was filtered, evaporated and purified by chromatography (ethyl acetate / hexane) to give (±) -1- (1,2-dithiolane-3-pentanoyloxy) -3- (z, z, z, z, z, z-docoza-4,7,10,13,16,19-hexenoyloxy) propane as a rye oil.

Example 18

Methyl [di (z, z, z-octadeca-6,9,12-trienoyloxypropyl) phosphate] (phosphotriester of 2 molecules of 3-hydroxypropyl ester of GLA and 1 molecule of methanol)

Part 1

Triethylamine (3.74 mL, 26.8 mmol) was added dropwise to a cold solution of freshly distilled phosphorus oxychloride (2.74 g, 17.9 mmol) in anhydrous tetrahydrofuran (15 mL). To this mixture was added dropwise a solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (5 g, 14.9 mmol) in anhydrous tetrahydrofuran (15 mL). The temperature was kept below 10 ° C while maintaining the reaction mixture under a nitrogen atmosphere. Thin layer chromatography after 15 minutes showed disappearance of starting materials. The mixture was filtered and evaporated. Toluene (50 mL) was added and the mixture was evaporated. Additional toluene (50 mL) was added and removed.

Part 2

A solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (3 g, 9 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to a solution of crude phosphochloridate (7.5 mmol) (half of the batch prepared in Part 1 above) and triethylamine (3.2 mL, 22.5 mmol) in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen. The reaction mixture was stored for 3 days at less than 10 ° C. Methanol (15 ml) was added and the reaction mixture was left at room temperature until thin layer chromatography showed completion of the phosphorochloridate reaction to give the desired phosphotyrstyrate. Purification by flash chromatography (ethyl acetate / hexane) gave methyl [di (z, z, z-octadeca-6,9,12-trienoyloxypropyl) phosphate] as a colorless oil.

Example 19

Di (z, z, z-octadeca-6,9,12-tricnoyloxypropyl) phosphate (phosphodiester of 2 molecules of 3-hydroxypropyl ester GLA)

Lithium bromide (104 mg, 1.13 mmol) in methyl ethyl ketone (1 mL) was added to a solution of methyl [di (z, z, z-octadeca-6,9,12-trienoyloxypropyl) phosphate] (0.85 g, 1 , 13 mmol) (prepared as in Example 18) in methyl ethyl ketone (1 mL) and the mixture was heated under reflux for 1 hour. After cooling, the mixture was dissolved in diethyl ether (3 mL) and extracted with water (3 mL). The formed emulsion was thawed by adding a few drops of methanol. The organic layer was separated, dried (sodium sulfate), evaporated and purified by flash chromatography (methanol / chloroform) to give di (z, z, z-octadeca-6,9,12-trienoyloxypropyl) phosphate as a waxy white solid. .

Example 20 (2-Aminoethyl) - (z, z, z-octadeca-6,9,12-trienoyloxypropyl) phosphate (ethanolamine phosphodiester and GLA 3-hydroxypropyl ester)

Part 1

A mixture of ethanolamine (0.5 mL, 8.25 mmol) and triethylamine (4.2 mL, 30 mmol) in anhydrous tetrahydrofuran (20 mL) was added to a solution of crude phosphochloridate (7.5 mmol) (half of the batch prepared in the above example). 18, part 1) in anhydrous tetrahydrofuran (20 mL) at less than 10 ° C. The progress of the reaction was monitored by thin layer chromatography. The mixture was stored for 3 days at a temperature below 5 ° C. After this time, it was filtered, evaporated, diluted with hexane (50 mL) and evaporated again.

Part 2

The product obtained in Part 1 was dissolved in isopropanol (100 mL), acetic acid (10 mL) and water (40 mL) and the solution was allowed to stand under nitrogen at room temperature. When thin layer chromatography showed that the reaction was complete, the mixture was evaporated and partitioned between acetonitrile (50 mL) and hexane (50 mL). The hexane layer was separated, evaporated and purified by flash chromatography (methanol / chloroform / water). Pure fractions were collected and evaporated. Addition of ethyl acetate excluded (2-aminoethyl) - (z, z, z-octadeca-6,9,12-trienoyloxypropyl) phosphate as a waxy cream colored solid which was collected by centrifugation.

Example 21 (z, z, z-Octadeca-6,9,12-trienoyloxypropyl) - [2- (N, N, N-trimethylammonium) ethyl] phosphate (choline phosphodiester and GLA 3-hydroxypropyl ester)

Part 1

2-Chloro-1,3,2-dioxaphospholane-2-oxide solution (430 mg,

3.4 mmol) in toluene (5 mL) was added to a cold (0 ° C) solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1, g, 2). , 98 mmol) and triethylamine (0.57 mL, 4.1 mmol) in toluene (45 mL). The mixture was stirred overnight and warmed to room temperature. Thin layer chromatography showed that the reaction was complete. Additional portions of triethylamine (0.3 mL) and 2-chloro-1,3,2-dioxaphospholane-2-oxide (200 mg) (as a solution in toluene (5 mL)) were added and the reactions were allowed to continue overnight. After this time, thin layer chromatography showed that the reaction was complete and the mixture was evaporated.

Part 2

The crude product from Part 1 was dissolved in acetonitrile (60 mL). A quarter of this solution (15 mL) and trimethylamine (10 mL) were heated in a sealed tube at 60 ° C for 5 hours (carefully). The reaction mixture was cooled and evaporated under a stream of nitrogen to give (ζ, ζ, ζ-octadeca-6,9,12-trienoyloxypropyl) - [2- (N, N, N-trimethylammonium) ethyl] phosphate.

Example 22 (z, z, z-Octadeca-6,9,12-trienoyloxypropyl) phosphate (3-hydroxypropyl ester GLA phosphomonoester)

A solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1.95 g, 5.8 mmol), pyridine (1.4 mL, 17.3 mmol) and anhydrous tetrahydrofuran (15 mL) was added dropwise with stirring to a cold (0 ° C) solution of phosphorus oxychloride (1.02 g, 6.6 mmol) in anhydrous tetrahydrofuran (5 mL) and the resulting mixture was kept at 0 ° C for 3 hours. Aqueous sodium bicarbonate (10% w / w, 10 mL) was added to the reaction mixture. After stirring for 20 minutes, the mixture was poured into ice / water (30 mL) and the solution was acidified to pH 1 by dropwise addition of 2M hydrochloric acid. The mixture was extracted with diethyl ether (2 x 30 mL). The ether extracts were combined, dried and evaporated. The resulting oil was azeotroped with dry pyridine to give (z, z, z-octadeca-6,9,12-trienoyloxypropyl) phosphate as a viscous yellow oil.

Example 23

Methyl [(z, z, z-octadeca-6,9,12-trienoyloxypropyl) - (α-tocopheryl) phosphate] (α-tocopherol phosphotriester, methanol and GLA 3-hydroxypropyl ester)

Part 1

Triethylamine (7.5 mL) was added to a solution of freshly distilled phosphorus oxychloride (1.26 g, 8.25 mmol) in anhydrous tetrahydrofuran (7.5 mL) at 0 ° C. After 15 minutes, a solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (2.5 g, 7.5 mmol) in 0 ° C was added dropwise over 30 minutes at 0 ° C. anhydrous tetrafuran (7.5 ml). Stirring was continued at this temperature for a further 30 minutes after the addition was complete. Α-tocopherol (3.23 g, 7.5 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise at 10 ° C, and the resulting mixture was then stirred at 10 ° C for 1 hour, and then warming to room temperature overnight. rooms.

Part 2

One quarter of the mixture prepared in Part 1, triethylamine (0.8 mL, 6 mmol) and methanol (10 mL) were stirred overnight under nitrogen at room temperature. The reaction mixture was evaporated and partitioned between ethyl acetate (30 mL) and water (20 mL), and sodium chloride and methanol were added to break the emulsion. The ethyl acetate layer was dried, evaporated and purified by flash chromatography (chloroform) to give methyl [(z, z, z-octadeca-6,9,12-trienoyloxypropyl) - (α-tocopheryl) phosphate].

Example 24 (z, z, z-Octadeca-6,9,12-trienoyloxypropyl) - (α-tocopheryl) phosphate (α-tocopherol phosphodiester and GLA 3-hydroxypropyl ester)

Triethylamine (2 mL) and water (5 mL) were added to a quarter of the reaction mixture prepared in Example 23, Part L. The mixture was stirred under nitrogen in an ice bath for 1 hour, acidified to pH 1 with 2M hydrochloric acid and extracted with ethyl acetate (20 mL). ) and methanol (5 mL). The extract was dried, evaporated and purified by flash chromatography (chloroform) to give (z, z, z-octadeca-6,9,12-trienoyloxypropyl) - (α-tocopheryl) phosphate.

Example 25

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -5- (z, z, z, z, z-icoza-5,8,11,14,17-pentenoyloxy) pentane (diester GLA and EPA with 1,5-pentanediol)

Part 1

To a solution of 1,5-dihydroxypentane (3.5 g) triethylamine (0.94 mL) and 4- (N, N-dimethylamino) pyridine (0.2 g) in methylene chloride (50 mL) was added dropwise from z-octadeca-6,9,12-trienoyl chloride (2 g) with stirring at 0 ° C under nitrogen. After completion of the reaction as shown by thin layer chromatography, the reaction mixture was washed with dilute hydrochloric acid and water, dried and purified by column chromatography to give 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -5-Hydroxypentane as a light yellow oil.

Part 2

As in Example 2, Part 2, but substituting 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane 1- (z, z, z-octadeca-6,9,12) -trienoyloxy) -3-hydroxypentane and z-octadeca-9-enoic acid z, z, z, z, z-icoza-5,8,11,14,17-pentenoic acid. Chromatography gave 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -5- (z, z, z, z, z-icoza-5,8,1,14,17-pentenoyloxy ) pentane as a light yellow oil.

Example 26

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -4- (z, z, z, z, z-icoza-5,8,11,14,17-pentenoxyoxy) benzene ( diester GLA and EPA with 1,4-dihydroxybenzene)

Preparation as in Example 25, Parts 1 and 2, but substituting 1,5-dihydroxypentane with 1,4-dihydroxybenzene in Part 1 and replacing methylene chloride with tetrahydrofuran as the solvent in Part 1. Chromatography gave 1- (z, z, z-octadeca). -6,9,12-trienoyloxy) -4- (z, z, z, z, z-icoza-5,8,11,14,17-pentenoyloxy) benzene as a pale yellow oil.

Example 27

1,4-Di (z, z, z-octadeca-6,9,12-trienyl) butane 1,4-dioate (diester of GLA alcohol with succinic acid)

Part 1

A solution of 1,8-diazabicyclo [5.4.0] undec-7-ene (0.54 mL) in dry tetrahydrofuran (10 mL) was added dropwise to a cold (0 ° C) solution of z, z, octadeca -6,9,12-trienol (1 g) and succinic anhydride (0.36 g) in dry tetrahydrofuran (20 ml). After completion of the reaction as shown by thin layer chromatography, the reaction mixture was diluted with diethyl ether and washed with dilute hydrochloric acid, water and brine. The organic layer was dried, evaporated and used directly in the second part of the reaction.

Part 2

A solution of 1,3-dicyclohexylcarbodiimide (0.83 g) and 4- (N, N-dimethylamino) pyridine (0.55 g) in methylene chloride (20 mL) was added to a solution of 1- (z, z, z-octadeca- 6,9,12-trienoyl) butane-1,4-dioate (1.32 g) az, z, z-octadeca-6,9,12-trienol (0.98 g) in methylene chloride (40 mL). After reaction as shown by TLC, the reaction mixture was diluted with hexane, filtered, evaporated and purified by chromatography to give 1,4-di (z, z, z-octadeca-6,9,12-trienyl) ) butane-1,4-dioate as a light yellow oil.

Example 28 2- (2-Methyl-5-nitroimidazolyl) ethyl-z, z, z-octadeca-6,9,12-trienoate (metronidazole ester with GLA)

Method A

To a suspension of metronidazole (206 g) in anhydrous acetonitrile (2300 mL) and anhydrous pyridine (107 mL) was added ζ, ζ, ζ-octadeca-6,9,12-trienoyl chloride (373 g) under stirring at room temperature under nitrogen. 30 minutes. Shortly after the addition of the acid chloride, a clear solution formed and stirring was continued for 2 hours. The mixture was allowed to stand overnight and the solvent was removed in vacuo (50 ° C / 20 mm Hg = 2.67 kPa). Ethyl acetate (1000 mL) was added to the residue, all precipitated solid was filtered off. The ethyl acetate solution was washed successively with sodium chloride solution, 2M hydrochloric acid, saturated aqueous sodium bicarbonate solution and finally with sodium chloride solution. After drying (sodium sulfate) the solvent was removed to give an orange oil. This material was subjected to dry column chromatography to give 2- (2-methyl-5-nitro-imidazolyl) ethyl-z, z, z-octadeca-6,9,12-trienoate as a pale yellow distillate oil.

Method B

Metronidazole (1.9 g) was suspended in toluene (30 mL) and the mixture was heated under reflux with a Dean-Stark trap for 20 minutes to remove any water present. To the boiling solution was added dropwise z, z, z-octadeca-6,9,12-trienoyl chloride (2.96 g) dropwise over 20 minutes. The mixture was stirred and heated under reflux for an additional 2 hours to give a dark reaction mixture. After cooling, the mixture was subjected to dry column chromatography to give 2- (2-methyl-5-nitroimidazolyl) ethyl-z, z, z-octadeca-6,9,12-trienoate as a pale yellow, distillate oil.

Example 29 2- (2-Methyl-5-nitroimidazolyl) ethyl-z, z-octadeca-9,12-dicnoate (metronidazole LA ester)

To a suspension of metronidazole (1.9 g) in dry dichloromethane (20 mL) was sequentially added 4- (N, N-dimethylamino) pyridine (1.22 g), 1,3-dicyclohexylcarbodiimide (2.2 g) and linoleic acid (2 g). 8 g) The mixture was stirred at room temperature overnight, 2M hydrochloric acid (20 ml) was added to the reaction mixture and stirring was continued After filtration, the organic layer was separated, washed with 50% saturated sodium chloride solution and finally saturated aqueous sodium chloride. The dichloromethane solution was dried (sodium sulphate) and evaporated in vacuo (30 ° C / 20 mm Hg = 2.67 kPa) Petrol (boiling point 30-60 ° C, 20 ml) was added to the residue and the mixture was stirred at room temperature. The mixture was allowed to stand at room temperature for 2 hours causing precipitation of residual urea, was removed by filtration and the filtrate was applied to a dry column to give 2- (2-methyl-5-nitroimidazolyl) ethyl-z, z-octadeca-9. 12-dienoate as light yellow, not distillate with oils.

Example 30 2- (2-Methyl-5-nitroimidazoloyl) ethyl-z, z, z-icoza-8,11,14-trienoate (metronidazole ester with DGLA)

Similarly, but substituting linoleic acid with the required amount of z, z, z-icoza-8,14,14-trenoic acid, 2- (2-methyl-5-nitroimidazoloyl) ethyl-z, z, z-icoza-8 was prepared. , 11,14--trienoate.

Example 31 2- (2-Methyl-5-nitroimidazoloyl) ethyl-z, z, z, z, z, -docoza-4,7,10,13,16,19-hexenoate (metronidazole ester with DHA)

Similarly, but substituting linoleic acid with the required amount of z, z, z, z, z, z-docoza-4,7,10,13,16,19-hexenoic acid, 2- (2-methyl-5-nitroimidazoloyl) was prepared. -ethyl-z, z, z, z, z, z-docoza-4,7,1,13,16,19-hexenoate.

Example 32 4- [3- / 2- (Trifluoromethyl) -10H-phenothiazin-10-yl] -1-piperazinetyl-z, z, z-octadeca-6,9,12-trienoate (flufenazine-GLA ester)

Similarly, but replacing metronidazole with the necessary amount of 4- [3- / 2- (trifluoromethyl) -10H-phenothiazin-10-yl] -1-piperazinetanol (flufenazine) and linoleic acid free base with the necessary amount of GLA, 4- [3- / 2- (trifluoromethyl) -10H-phenothiazine-10-yl /] - l-piperazinetyl-z, z, z-octadeca-6,9,12-trienoate.

Example 33 4,4 '- [bis- (z, z, z-octadeca) -6,9,12-trienoylamino] diphenylsulfone (dapsone bis-amide with GLA)

In a similar manner, but substituting metronidazole with the required amount of 4,4'-diaminodiphenylsulfone (dapsone) and linoleic acid with the necessary amount of GLA, 4,4 '- [bis- (z, z, z-octadeca) -6,9,12- trienoylamino] diphenyl sulfone.

Example 34 N-Methyl-3-phenyl-3- [α, α, α-trifluoro-p-tolyl] propyl-z, z, z-octadeca-6,9,12-trienamide (fluoxetine amide with GLA)

In a similar manner, but substituting the required amount of N-methyl-3-phenyl-3- [α, α, α-trifluoro-p-tolyl] propylamine (fluoxetine) and linoleic acid with the required amount of GLA, methanidazole required N-methyl-3- phenyl-3- [a, a, a-trifluoro-p-tolyl] propyl-z, z, z-octadeca-6,9,12-triénamid.

Example 35 trans-1- (z, z, z-Octadeca-6,9,12-trienoylamino) 2-phenylcyclopropane (tranylcypromine amide with GLA)

In a similar manner, but replacing metronidazole with the necessary amount of trans-1-amino-2-phenylcyclopropane (tranylcypromine) and linoleic acid with the necessary amount of GLA, trans-1- (z, z, z-octadeca-6,9,12-trienoylamino) was prepared. -2-phenylcyclopropane.

Example 36 z, z, z-Octadeca-6,9,12-trienamide 6 - [(aminophenylacetyl) amino] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid (ampicillin amide with GLA)

Triethylamine (0.3 mL) was added to a stirred suspension of ampicillin (0.7 g) in anhydrous dimethylformamide (120 mL) under a nitrogen atmosphere. To the resulting clear solution was added z, z, z-octadeca-6,9,12-trienic acid, N-hydroxysuccinimide ester (0.75 g), maintaining the reaction mixture at 0-10 ° C. The reaction mixture was stirred at this temperature for an additional hour before the mixture was allowed to stand at room temperature overnight. Thin layer chromatography (40% tetrahydrofuran in hexane) at this point showed that most of the succinimide esters had reacted. Water (40 mL) was added to the reaction flask and mixed. The solution was then neutralized and extracted with ethyl acetate. The extract was washed with water, dried (sodium sulfate) and evaporated to dryness to give the crude product as a yellow glass. Trituration with hexane gave z, z, z-octadeca-6,9,12-trienamide 6 - [(aminophenylacetyl) amino] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.1] O] heptane-2-carboxylic acid as a yellow powder.

Example 37 z, z, z-octadeca-6,9,12-trienyl-z, z, z-octadeca-6,9,12-trienoate (GLA ester with GLA alcohol)

1,3-Dicyclohexylcarbodiimide (0.82 g) and 4- (N, N-dimethylamino) pyridine (0.48 g) in methylene chloride (5 mL) were added to a solution of z, z, z-octadeca-6.9, 12-tricnol (0.95 g) az, z, z-octadeca-6,9,12-trienic acid (1 g) in methylene chloride (10 mL) with stirring at room temperature under nitrogen. After reaction as shown by TLC, hexane was added to the reaction mixture, which was then filtered and purified by column chromatography to obtain from, z, z-octadeca-6,9,12-trienyl-z. , z, z-octadeca-6,9,12-trienoate as a pale yellow oil.

Example 38 z, z, z-Octadeca-6,9,12-trienyl-z, z, z, z, z-icoza-5,8,11,14,17-pentenoate (EPA ester with GLA alcohol)

Prepared as in Example 37 but substituting ζ, ζ, ζ-octadeca-6,9,12-trienoic acid z, z, z, z, z-icoza-5,8,1,1,14,17-pentenoic acid .

Example 39

2-Methyl-3- (z, z, z, z, z-icoza-5,8,1,14,17-pentenoyloxy) -4-formyl-5- (z, z, z, z, z- icoza-5,8,1,14,17-penteneyloxy) methylpyridine (pyridoxal di-EPA ester)

To a suspension of pyridoxal hydrochloride (1.0 g) in methylene chloride (20 mL) was added triethylamine (2.0 mL). A clear yellow solution was formed. Z, z, z, z, z-icoza-5,8-1,14,17-pentenoyl chloride (1.73 g) (prepared by reaction of EPA with oxalyl chloride in methylene chloride) was added under ice-cooling. The mixture was stirred under nitrogen overnight while warming to room temperature. After diluting with an equal volume of methylene chloride, the mixture was extracted with 2M hydrochloric acid (20 ml), washed with water (3 x 20 ml), dried and evaporated. Purification by chromatography (ethyl acetate / hexane) gave 2-methyl-3- (z, ζ, ζ, z, z-icoza-5,8,11,14,17-pentenoyloxy) -4-formyl-5- (z, z) , z, z, z-icoza-5,8,11,14,17-pentenoyloxy) methylpyridine as a clear oil.

Example 40 2-Methyl-3-hydroxy-4-formyl-5- (z, z, z-octadeca-6,9,12-trienoyloxy) methylpyridine (pyridoxal GLA ester)

A solution of ζ, ζ, ζ-octadeca -6,9,12-trienoyl chloride (800 mg, 2.7 mmol) in methylene chloride (10 mL) was added slowly dropwise to a mixture of pyridoxal hydrochloride (500 mg, 2.45 mmol), triethylamine (1 mL, 7.2 mmol) and 4- (N, N-dimethylamino) -pyridine (several mg, catalytic amount) in methylene chloride (20 mL) at 0 ° C under nitrogen after reaction as determined by TLC. The mixture was evaporated and purified by chromatography (ethyl acetate / hexane) to give 2-methyl-3-hydroxy-4-formyl-5- (z, z, z-octadeca-6,9,12-trienoyloxy) methylpyridine as colorless oil, which subsequently solidified.

Example 41 2-Methyl-3-hydroxy-4,5-di (z, z, z-octadeca-6,9,12-trienoyloxy) methylpyridine (pyridoxine bis-GLA ester)

Solution of z, z, z-octadeca-6,9,12-trienoyl chloride (650 mg,

2.2 mmol) in methylene chloride (10 mL) was added slowly dropwise to a mixture of pyridoxine hydrochloride (206 mg, 1 mmol), triethylamine (0.7 mL, 5 mmol) and 4- (N, N-dimethylamino) -pyridine ( a few mg, catalytic amount) in methylene chloride (20 mL) at 0 ° C under nitrogen. After reaction (4 hours) as determined by thin layer chromatography, the mixture was evaporated and purified by flash chromatography (ethyl acetate / hexane) to give 2-methyl-3-hydroxy-4,5-di (z, z) , z-octadeca-6,9,12-trienoyloxy) methylpyridine as a colorless oil.

Example 42 1- [2- (2-Methyl-5-nitroimidazoloyl) ethyl] -4- (z, z, z-octadeca-6,9,12-trienyl) budan-1,4-dioate (metronidazole diester and GLA alcohol with succinic acid)

A solution of 1,3-dicyclohexylcarbodiimide (780 mg, 3.8 mmol) and 4- (N, N-dimethylamino) pyridine (530 mg, 4.3 mmol) in methylene chloride (15 mL) was added to the GLA alcohol monoester solution with stirring. and succinic acid (1.25 g,

3.3 mmol) (prepared as in Example 27, part 1) and metronidazole (620 mg, 3.6 mmol) in methylene chloride (30 mL) at room temperature under nitrogen. After completion of the reaction as shown by TLC, the mixture was diluted with hexane, filtered, evaporated and purified by flash chromatography (ethyl acetate / hexane). Product fractions were collected and evaporated to give 1- [2- (2-methyl-5-nitroimidazoloyl) ethyl] -4- (z, z, z-octadeca-6,9,12-trienyl) butane-1, m.p. 4-dioate as a colorless oil.

Example 43 trans-1- (z, z, z-Octadeca-6,9,12-trienyloxycarbonylbutoxyamino) -2-phenylcyclopropane (succinic acid, 1-GLA alcohol ester, 4-tranylcyprominamide)

A solution of 1,3-dicyclohexylcarbodiimide (315 mg, 1.52 mmol) and 4- (N, N-dimethylamino) pyridine (210 mg, 1.72 mmol) in methylene chloride (10 mL) was added to the GLA alcohol monoester solution with stirring. and succinic acid (500 mg, 1.32 mmol) (prepared as in Example 27, part 1) and tranylcypromine (225 mg, 1.32 mmol) in methylene chloride (20 mL) at room temperature under nitrogen. After completion of the reaction as shown by TLC, the mixture was diluted with hexane, filtered, evaporated and purified by flash chromatography (ethyl acetate / hexane). The product fractions were collected and evaporated to give trans-1- (z, z, z-octadeca-6,9,12-trienyloxycarbonylbutoxyamino) -2-phenylcyclopropane as a colorless oil.

Example 44 (±) -2,5,7,8-Tetramethyl-2- (4 ', 8', 12'-trimethyldecyl) -6-chromanyl-z, z, z-octadeca-6,9,12-trienoate (Α-tocopherol GLA ester) z, z, z-Octadeca-6,9,12-trienoyl chloride (2.96 g, 10 mmol) was added dropwise with stirring over 2 to 3 minutes to the (±) -a- solution. tocopherol (4.3 g, 10 mmol) and pyridine (0.885 mL, 11 mmol) in methylene chloride (35 mL) under nitrogen at -5 ° C. The reaction mixture was stirred overnight while warming to room temperature. Thin layer chromatography showed that the reaction was essentially complete. The reaction mixture was washed with water (100 mL), 2M hydrochloric acid (10 mL in 100 mL water) and water (4 x 100 mL). The organic layer was dried (sodium sulfate) and evaporated. Purification by flash chromatography (ether / hexane) gave (±) -2,5,7,8-tetramethyl-2- (4 ', 8', 12'-trimethyldecyl) -6-chromanyl-z, z, octadeca -6,9,12-trienoate as a pale yellow oil.

Example 45

Androst-5-en-17-one-3- (z, z, z, z, z, z-docoza-4,7,10,13,16,19-hexenoate) (dehydroepiandrosterone DHA ester)

To a cold mixture of (0 ° C) dehydroepiandrosterone (1 g) and triethylamine (1 mL) in methylene chloride (20 mL) was added z, z, z, z, z, z-docoza-4,7,10,13,16 19-hexenoyl chloride (1.33 g) (prepared by reaction of DHA with oxalyl chloride in methylene chloride). The mixture was stirred overnight at room temperature, then diluted with methylene chloride (20 mL), extracted with 2M hydrochloric acid (20 mL), washed with water (2 x 20 mL), dried and evaporated. Purification by flash chromatography (ethyl acetate / hexane) gave dehydroepiandrost-5-en-17-one-3- (z, z, z, z, z, z-docoza-4,7,10,13,16,19- hexenoate) as a clear oil.

Example 46 z, z, z-Octadeca-6,9,12-trienyl [2- (z, z, z-octadeca-6,9,12-trienoyloxy) acetate] (diester of GLA and GLA alcohol with glycolic acid)

Part 1

A solution of chloroacetyl chloride (0.4 mL, 5 mmol) in methylene chloride (10 mL) was added dropwise to a solution of z, z, z-octadeca-6,9,12-trienol (1 g, 3.8 mmol) and thietylamine ( 1.4 mL, 10 mmol) in methylene chloride (20 mL) at 0 ° C. The progress of the reaction was monitored by thin layer chromatography. After 3 hours the reaction was essentially complete but not complete. A few drops of chloroacetyl were added. TLC analysis over 5 minutes showed the reaction was complete. The mixture was washed with water (2 x 50 mL) and brine (50 mL), dried (sodium sulfate) and evaporated. Toluene (50 mL) was added to azeotropically remove the last water residue. This gave the chloroacetyl GLA alcohol as a dark brown oil, which was used without further purification.

Part 2

A mixture of z, z, z-octadeca-6,9,12-trienoic acid (700 mg,

2.5 mmol) and cesium carbonate (410 mg, 1.25 mmol) were stirred in methanol until a clear solution was obtained. The mixture was then evaporated and stored at 40 ° C under high vacuum for 1 hour. This gave the GLA cesium salt, which was used without further purification.

Part 3

To a flask containing GLA cesium salt, as prepared in Part 2, was added GLA alcohol chloroacetate (Part 1) (500 mg, 1.5 mmol) and dry dimethylformamide (15 mL). The reaction mixture was stirred under nitrogen at room temperature. After 90 minutes, thin layer chromatography showed that the reaction was complete. The reaction mixture was extracted with hexane (2 x 40 mL), and the hexane extract was washed with brine (2 x 50 mL) and water (50 mL), dried (sodium sulfate) and evaporated to yield z, z-octadeca. -6,9,12-trienyl- [2- (z, z, z-octadeca-6,9,12-trienoyloxy) acetate] as a colorless oil.

Example 47

Hydrocortisone-21 - (z, z, z-octadeca-6,9,12-trienoate) (Hydrocortisone GLA ester)

A solution of z, z, z-octadeca-6,9,12-trienoyl chloride (450 mg, 1.52 mmol) in methylene chloride (10 mL) was added slowly dropwise to a mixture of hydrocortisone (500 mg, 1.38 mmol), triethylamine (420 μΐ, 3 mmol) and 4- (N, N-dimethylamino) pyridine (several mg, catalytic amount) in methylene chloride (20 mL) at 0 ° C under nitrogen. Thin layer chromatography after 4 hours showed that the reaction was complete. The mixture was evaporated and purified by chromatography (ethyl acetate / hexane) to give hydrocortisone-21- (z, z, z-octadeca-6,9,12-trienoate) as a colorless oil.

Example 48 z, z, z-Octadeca-6,9,12-trienyl- [2- / 1- (4-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetyloxy] acetate] (indomethacin diester and GLA alcohol with glycolic acid)

Part 1

A mixture of indomethacin (895 mg, 2.5 mmol) and cesium carbonate (410 mg, 1.25 mmol) was stirred in methanol until a clear solution formed. The solution was then evaporated and stored at 40 ° C under high vacuum for 1 hour. This gave the cesium salt of indomethacin as a light yellow solid.

Part 2

To a flask containing indomethacin cesium salt as prepared in Part 1 was added GLA alcohol chloroacetate (prepared as in Example 46, Part 1) (500 mg,

1.5 mmol) and dry dimethylformamide (15 mL). The reaction mixture was stirred under nitrogen at room temperature, the progress of the reaction was followed by thin layer chromatography. After the reaction mixture was refrigerated overnight, thin layer chromatography analysis indicated that the reaction was complete. The mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). Several ml of sodium chloride solution was added to break the emulsion. The ethyl acetate layer was washed with water (3 x 50 mL), dried (sodium sulfate), filtered through a pad of silica and evaporated to yield from z, z-octadeca-6,9,12-trienyl- [2- / l]. (4-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetyloxy / acetate] as a pale yellow oil.

Example 49 1- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (4-phenylbutanoyloxy) propane (4-phenylbutanoic acid diester and GLA with 1,3-propanediol)

A solution of 1,3-dicyclohexylcarbodiimide (710 mg, 3.45 mmol) and 4- (N, N-dimethylamino) pyridine (475 mg, 3.9 mmol) in methylene chloride (10 mL) was added to a solution of 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3-hydroxypropane (1 g, 3 mmol) and 4-phenylbutyric acid (520 mg, 3.15 mmol) in methylene chloride (15 mL). The resulting mixture was stirred at room temperature under nitrogen until the reaction was complete as evidenced by thin layer chromatography. The mixture was filtered, evaporated and purified by flash chromatography to give 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3- (4-phenylbutanoyloxy) propane.

Example 50

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (phenylacetoxy) propane (phenylacetic diester and GLA with 1,3-propanediol)

In a similar manner to Example 49 but substituting phenylacetic acid for 4-phenylbutanoic acid (430 mg, 3.15 mmol), 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3 - ( fenylacetoxyjpropán.

Example 51

- (z, z, z-Octadeca-6,9,12-trienoyloxy) -3- (trans-cinnamoyloxy) propane (diester of trans-cinnamic acid and GLA with 1,3-propanediol)

In a similar manner to Example 49, but substituting trans-cinnamic acid for 4-phenylbutyric acid (470 mg, 3.15 mmol), 1- (z, z, z-octadeca-6,9,12-trienoyloxy) -3- (trans-cinnamoyloxy) propane.

There are no claims for compounds including niacin which are the subject of another co-pending application.

Without limiting the generality of the foregoing, but subject to the foregoing limitation of the scope of the claims, the following aspects of the invention are claimed.

Claims (8)

PATENT CLAIMS L 1,3-Propanediol derivative of structure (I) CH ₂ OR 1 I ch ₂ I CH ₂ OR 2 in which R ¹ comprises an acyl group or an aliphatic alcohol group derived from a fatty acid having 12 to 30 carbon atoms, preferably 16 to 30 carbon atoms, with two or more cis- or trans-double bonds, and R ² is a hydrogen atom, or includes an acyl group or an aliphatic alcohol group such as R ¹ , the same or different, or a nutritional, medicinal or other biologically active residue for use as a medicament. The 1,3-propanediol derivative according to claim 1, wherein a phosphate, succinate or other difunctional acidic group is interposed between the group R ¹ and / or R ² and the rest of the 1,3-propanediol, especially when R ^{2 is a} nutritional, medicinal or other a biologically active moiety having a hydroxyl or amine function. The 1,3-propanediol derivative according to claim 1 or 2, wherein the fatty acid is selected from the group consisting of essential fatty acids of the n-6 or n-3 series or oleic acid, columbinic acid, parinaric acid or conjugated linoleic acid. The 1,3-propanediol derivative according to claim 3, wherein the fatty acid is selected from the group consisting of gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, stcaridonic acid, icosapentenoic acid, n-3 docosapentenoic acid. , docosahexenoic acid or conjugated linoleic acid. The 1,3-propanediol derivative according to claim 2, comprising two residues derived from fatty acids, one fatty acid being gamma-linolenic acid or dihomo-gamma-linolenic acid and the other being gamma-linolenic acid, dihomo-gamma- linolenic acid, stearidonic acid, icosapentenic acid, docosahexenic acid, conjugated linoleic acid or columbinic acid for use as a medicament for the treatment of: (a) complications of diabetes, in particular neuropathy and retinopathy; and improving insulin responses in diabetes and pre-diabetes; b) cancers; c) osteoarthritis; d) rheumatoid arthritis; (e) other inflammatory and autoimmune diseases including Sjogren's syndrome, systemic lupus, ulcerative colitis, Crohn's disease and uveitis; (f) respiratory diseases including asthma; (g) neurological disorders, including multiple sclerosis; Parkinson's disease and Huntington's chorea; h) renal and urinary disorders; (i) cardiovascular diseases; j) degenerative eye diseases including retinitis pigmentosa and senile macular degeneration; (k) mental illnesses, including schizophrenia, Alzheimer's, concentration disorders, alcoholism and depression; l) prostatic hypertrophy and prostatitis; (m) impotence and male infertility; n) mastalgia; o) male baldness; p) osteoporosis; SK 285135-6 (q) dermatological disorders, including atopic eczema, hand eczema, psoriasis, urticaria and allergic disorders; (r) dyslexia and other learning disabilities; and s) cancer cachexia. The 1,3-propanediol derivative according to claim 1, comprising two fatty acid residues, one fatty acid is arachidonic acid and the other is arachidonic acid, gamma-linolenic acid, docosahexenic acid, dihomo-gamma-linolenic acid or acid. icosapentene for use as a medicament for the treatment of the disorders mentioned in claim 5 and in particular a), g), i), j), k), q) and ar). The 1,3-propanediol derivative according to claim 1, comprising two fatty acid moieties, one fatty acid being icosapentenoic acid and the other being icosapentenic acid or docosahexenic acid for use as a medicament for the treatment of any of the disorders mentioned in claim 5, but in particular (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (p), (r) and (s). The 1,3-propanediol derivative according to claims 5 to 7, for the use of a diol moiety contained therein as a food ingredient, in particular a functional food or nutraceutical for health promotion, as a food supplement or as an ingredient in food.